Publications by authors named "Lin Shi"

706 Publications

A High-Throughput Comparative Proteomics of Milk Fat Globule Membrane Reveals Breed and Lactation Stages Specific Variation in Protein Abundance and Functional Differences Between Milk of Saanen Dairy Goat and Holstein Bovine.

Front Nutr 2021 28;8:680683. Epub 2021 May 28.

School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an, China.

Large variations in the bioactivities and composition of milk fat globule membrane (MFGM) proteins were observed between Saanen dairy goat and Holstein bovine at various lactation periods. In the present study, 331, 250, 182, and 248 MFGM proteins were characterized in colostrum and mature milk for the two species by Q-Orbitrap HRMS-based proteomics techniques. KEGG pathway analyses displayed that differentially expressed proteins in colostrum involved in galactose metabolism and an adipogenesis pathway, and the differentially expressed proteins in mature milk associated with lipid metabolism and a PPAR signaling pathway. These results indicated that the types and functions of MFGM proteins in goat and bovine milk were different, and goat milk had a better function of fatty acid metabolism and glucose homeostasis, which can enhance our understanding of MFGM proteins in these two species across different lactation periods, and they provide significant information for the study of lipid metabolism and glycometabolism of goat milk.
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http://dx.doi.org/10.3389/fnut.2021.680683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193056PMC
May 2021

Efficacy and safety of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy or antiangiogenic therapy as first-line treatment in patients with EGFR-mutant non-small cell lung cancer: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jun 10:103393. Epub 2021 Jun 10.

The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China. Electronic address:

Objective: We conducted a meta-analysis to synthesize the results of published randomized controlled trials conducted to evaluate the efficacy and safety of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy or antiangiogenic therapy.

Methods: PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov databases were searched and literatures from international conferences were read to identify eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS) and treatment-emergent adverse events (TEAEs).

Results: 10 studies, all on first-generation EGFR-TKI combination therapy, involving 2367 patients were included. Combination therapy resulted in significant improvements in ORR (RR: 1.11, 95 % CI: 1.06-1.17, P < 0.001), DCR (RR: 1.03, 95 % CI: 1.01-1.05, P = 0.007), PFS (HR: 0.56, 95 % CI: 0.51-0.62, P < 0.001), OS (HR: 0.74, 95 % CI: 0.64-0.84, P = 0.002) over monotherapy. This improvement was more apparent in the EGFR-TKIs combination chemotherapy group, and indirect comparisons revealed that EGFR-TKIs combined with chemotherapy appeared to be superior to combined with antiangiogenic therapy in ORR (RR: 1.19, 95 % CI: 1.07-1.32), DCR (RR: 1.04, 95 % CI: 1.02-1.08), and OS (HR: 0.79, 95 % CI: 0.66-0.96). Of additional concern is the increased incidence of TEAEs in combination therapy.

Conclusion: As a first-line treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), first-generation EGFR-TKIs combined with chemotherapy or antiangiogenic therapy was associated with significant improvement in ORR, DCR, PFS and OS compared with monotherapy.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103393DOI Listing
June 2021

Integrative Analysis of Genome, 3D Genome, and Transcriptome Alterations of Clinical Lung Cancer Samples.

Genomics Proteomics Bioinformatics 2021 Jun 8. Epub 2021 Jun 8.

Center for Bioinformatics, School of Life Sciences, Center for Statistical Science, Peking University, Beijing 100871, China. Electronic address:

Genomic studies of cancer cell alterations, such as mutations, copy number variations (CNVs), and translocations, greatly promote our understanding of the genesis and development of cancer. However, the 3D genome architecture of cancers remains less studied due to the complexity of cancer genomes and technical difficulties. To explore the 3D genome structure in clinical lung cancer, we performed Hi-C experiments using paired normal and tumor cells harvested from patients with lung cancer, combining with RNA-seq analysis. We demonstrated the feasibility of studying 3D genome of clinical lung cancer samples with a small number of cells (1 × 10), compared the genome architecture between clinical samples and cell lines of lung cancer, and identified conserved and changed spatial chromatin structures between normal and cancer samples. We also showed that Hi-C data can be used to infer CNVs and point mutations in cancer. By integrating those different types of cancer alterations, we showed significant associations between CNVs, 3D genome, and gene expression. We propose that 3D genome mediates the effects of cancer genomic alterations on gene expression through altering regulatory chromatin structures. Our study highlights the importance of analyzing 3D genomes of clinical cancer samples in addition to cancer cell lines and provides an integrative genomic analysis pipeline for future larger-scale studies in lung cancer and other cancers.
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http://dx.doi.org/10.1016/j.gpb.2020.05.007DOI Listing
June 2021

Viperin_sv1 promotes RIG-I expression and suppresses SVCV replication through its radical SAM domain.

Dev Comp Immunol 2021 Jun 8;123:104166. Epub 2021 Jun 8.

College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, Hubei, China; Hubei Engineering Technology Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan, 430070, Hubei, China. Electronic address:

SVCV infection is known to activate the host's innate immune responses, including the production of interferon (IFN) and interferon-stimulated genes (ISGs). Viperin_sv1 is a novel splice variant of viperin, which is induced during SVCV infection and proves to positively regulate the IFN activation and production. However, the underlying mechanism remains unsolved. In this study, the P protein of SVCV was identified to be the key to induce the mRNA modification and production of viperin_sv1 during the virus infection. Besides, Viperin_sv1 was able to trigger the RLR signaling cascades to activate type-1 interferon response. Additional analysis revealed that viperin_sv1 promoted the stability and function of RIG-I, which result in the production of IFN and ISGs. Moreover, the central SAM domain of viperin_sv1 was demonstrated to be essential for regulating RIG-I protein expression and inducing IFN production. Furthermore, this study also showed that SVCV replication could be inhibited by the viperin_sv1 SAM domain. In conclusion, our study demonstrates that viperin_sv1 reduces the replication of SVCV by promoting the RIG-I protein expression. Our findings identified the antiviral function played by the SAM domain of viperin_sv1 and suggested an antiviral mechanism that is conserved among different species.
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http://dx.doi.org/10.1016/j.dci.2021.104166DOI Listing
June 2021

MRI-based Alzheimer's disease-resemblance atrophy index in the detection of preclinical and prodromal Alzheimer's disease.

Aging (Albany NY) 2021 05 25;13(10):13496-13514. Epub 2021 May 25.

Division of Neurology, Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China.

Alzheimer's Disease-resemblance atrophy index (AD-RAI) is an MRI-based machine learning derived biomarker that was developed to reflect the characteristic brain atrophy associated with AD. Recent study showed that AD-RAI (≥0.5) had the best performance in predicting conversion from mild cognitive impairment (MCI) to dementia and from cognitively unimpaired (CU) to MCI. We aimed to validate the performance of AD-RAI in detecting preclinical and prodromal AD. We recruited 128 subjects (MCI=50, CU=78) from two cohorts: CU-SEEDS and ADNI. Amyloid (A+) and tau (T+) status were confirmed by PET (C-PIB, F-T807) or CSF analysis. We investigated the performance of AD-RAI in detecting preclinical and prodromal AD (i.e. A+T+) among MCI and CU subjects and compared its performance with that of hippocampal measures. AD-RAI achieved the best metrics among all subjects (sensitivity 0.74, specificity 0.91, accuracy 85.94%) and among MCI subjects (sensitivity 0.92, specificity 0.81, accuracy 86.00%) in detecting A+T+ subjects over other measures. Among CU subjects, AD-RAI yielded the best specificity (0.95) and accuracy (85.90%) over other measures, while hippocampal volume achieved a higher sensitivity (0.73) than AD-RAI (0.47) in detecting preclinical AD. These results showed the potential of AD-RAI in the detection of early AD, in particular at the prodromal stage.
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http://dx.doi.org/10.18632/aging.203082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202853PMC
May 2021

Binding between ROCK1 and DCTN2 triggers diabetes‑associated centrosome amplification in colon cancer cells.

Oncol Rep 2021 Jul 3;46(1). Epub 2021 Jun 3.

Institute of Biomedical Sciences of The School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P.R. China.

Type 2 diabetes increases the risk various types of cancer and is associated with a poor prognosis therein. There is also evidence that the disease is associated with cancer metastasis. Centrosome amplification can initiate tumorigenesis with metastasis and increase the invasiveness of cancer cells . Our previous study reported that type 2 diabetes promotes centrosome amplification via the upregulation and centrosomal translocation of Rho‑associated protein kinase 1 (ROCK1), which suggests that centrosome amplification is a candidate biological link between type 2 diabetes and cancer development. In the present study, functional proteomics analysis was used to further investigate the molecular pathways underlying centrosome amplification by targeting ROCK1 binding partners. High glucose, insulin and palmitic acid were used to induce centrosome amplification, and immunofluorescent staining was employed to visualize centrosomal alterations. Combined with immunoprecipitation, mass spectrometry‑based proteomics analysis was used to identify ROCK1 binding proteins, and protein complex disruption was achieved by siRNA‑knockdown. In total, 1,148 ROCK1 binding proteins were identified, among which 106 proteins were exclusively associated with the treated samples, 193 were only associated with the control samples, and 849 were found in both the control and treated samples. Of the proteins with evidence of centrosomal localization, Dynactin subunit 2 (DCTN2) was confirmed to be localized to the centrosomes. Treating the cells with high glucose, insulin and palmitic acid increased the protein levels of ROCK1 and DCTN2, promoted their binding with each other, and triggered centrosome amplification. Disruption of the protein complex by knocking down ROCK1 or DCTN2 expression partially attenuated centrosome amplification, while simultaneous knockdown of both proteins completely inhibited centrosome amplification. These results suggested ROCK1‑DCTN2 binding as a signal for the regulation of centrosome homeostasis, which is key for diabetes‑associated centrosome amplification, and enriches our knowledge of centrosome biology. Therefore, the ROCK1‑DCTN2 complex may serve as a target for inhibiting centrosome amplification both in research or future therapeutic development.
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http://dx.doi.org/10.3892/or.2021.8102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185503PMC
July 2021

Accurate Quantification of Sulfonamide Metabolites in Goat Meat: A New Strategy for Minimizing Interaction between Sheep Serum Albumin and Sulfonamide Metabolites.

J Agric Food Chem 2021 Jun 3;69(23):6556-6568. Epub 2021 Jun 3.

School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.

To date, the determination of sulfonamide metabolites in animal-derived food has universal disadvantages of low throughput and no integrated metabolites involved. In this study, a powerful and reliable strategy for high-throughput screening of sulfonamide metabolites in goat meat was proposed based on an aqueous two-phase separation procedure (ATPS) combined with ultrahigh-performance liquid chromatography quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap). Noncovalent interactions including van der Waals force, hydrogen bonding, and hydrophobic effect were determined to be staple interactions between the sulfonamide metabolites and sheep serum albumin by fluorescence spectroscopy and molecular docking technology, and an 80% acetonitrile-water solution/(NH)SO was used as ATPS in order to release combined sulfonamide metabolites and minimize the influence of sheep serum albumin. Sulfonamide metabolites in the matrix were screened based on a mechanism of mass natural loss and core structure followed by identification combined with the pharmacokinetic. The developed strategy was validated according to EU standard 2002/657/EC with CCα ranging from 0.07 to 0.98 μg kg, accuracy recovery with 84-107%, and RSDs lower than 8.9%. Eighty seven goat meat samples were used for determination of 26 sulfonamides and 8 potential metabolites. On the basis of the established innovative process, this study has successfully implemented the comprehensive detection of sulfonamide metabolites, including -acetylated substitution, -hydroxylation, 4-nitroso, azo dimers, oxidized nitro, monoglucose conjugation, β-d-glucuronide, and -4-aminobenzenesulfonyl metabolites, which were shown to undergo oxidation, hydrogenation, sulfation, glucuronidation, glucosylation, and -aminomethylation.
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http://dx.doi.org/10.1021/acs.jafc.1c02496DOI Listing
June 2021

Distinct metabolite profiles of adiposity indices and their relationships with habitual diet in young adults.

Nutr Metab Cardiovasc Dis 2021 Apr 5. Epub 2021 Apr 5.

Department of Epidemiology and Biostatistics, School of Public Health, Global Health Institute, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, 710061, Xi'an, Shaanxi, China; Nutrition and Food Safety Engineering Research Center of Shaanxi Province, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, 76 West Yanta Road, 710061, Xi'an, Shaanxi, China. Electronic address:

Background And Aims: Obesity is characterized as overall or regional adiposity accumulation. However, the metabolic status underlying fat accumulation was not well understood. We sought to identify metabolite profiles based on their correlations with body mass index (BMI), body fat percentage (BFP), waist circumference (WC), and visceral adiposity index (VAI) in young Chinese adults (19-37 years old), and their associations with dietary consumption were also explored.

Methods And Results: A total of 86 plasma samples were analyzed using untargeted lipidomics and metabolomics approaches. Metabolite profiles of adiposity indices were identified using random forest modelling. Ridge regression was used to generate metabolite scores. Overall, 30, 46, 30, and 20 metabolites correlated with BMI, BFP, WC, and VAI, respectively, which resulted in metabolite scores for each index. Top three enriched categories of the identified metabolites were glycerophospholipids, glycerolipids, and sphingolipids, with some specific metabolites (such as phosphatidylserine (37:2), phatidylethanolamine (42:4), and ceramide (40:0)) exclusively associated with overall adiposity, and some other metabolites exclusively associated with abdominal adiposity indices, e.g., triradylglycerol (45:0, 52:4, and 35:0) and diacylglycerol (38:4, 36:3, and 36:5). Moreover, metabolite scores were negatively associated with the intake of food rich in protein or fiber, while they were positively associated with food rich in carbohydrate, with similar results for adiposity indices.

Conclusion: We observed unique metabolite profiles of regional or overall fat deposition in young adults. Glycerophospholipids, glycerolipids, or sphingolipids may be involved in the regulation of adiposity accumulation, affected by dietary exposures.
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http://dx.doi.org/10.1016/j.numecd.2021.03.025DOI Listing
April 2021

AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake.

Cell Death Differ 2021 May 27. Epub 2021 May 27.

Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.
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http://dx.doi.org/10.1038/s41418-021-00809-9DOI Listing
May 2021

UHPLC-Q-Orbitrap HRMS-based quantitative lipidomics reveals the chemical changes of phospholipids during thermal processing methods of Tan sheep meat.

Food Chem 2021 Oct 18;360:130153. Epub 2021 May 18.

School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.

Thermal processing affects the lipid compositions of meat products. The study determined the effects of boiled, steamed and roasted processing methods on the lipidomics profiles of Tan sheep meat with a validated UPLC-Q-Orbitrap HRMS combined lipid screening strategy method. Combined with sphingolipid metabolism, the boiled approach was the suitable choice for atherosclerosis patients for more losses of sphingomyelin than ceramide in meat. The similarly less losses of phosphatidylcholine and lysophosphatidylcholine showed in glycerophospholipid metabolism implied that steamed Tan sheep meat was more suitable for the populations of elderly and infants. Furthermore, a total of 90 lipids with significant difference (VIP > 1) in 6 lipid subclasses (sphingomyelin, ceramide, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamines, triacylglycerol,) were quantified among raw and three types of thermal processed Tan sheep meat, further providing useful information for identification of meat products with different thermal processing methods (LOD with 0.14-0.31 μg kg, LOQ with 0.39-0.90 μg kg).
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http://dx.doi.org/10.1016/j.foodchem.2021.130153DOI Listing
October 2021

High-density lipoprotein cholesterol and brain aging among rural-dwelling older adults: a population-based MRI study.

Eur J Neurol 2021 May 25. Epub 2021 May 25.

Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.

Background: Current evidence supports the involvement of lipids in brain aging. We explore a range of serum lipids in association with brain structure and cognitive function among rural-dwelling older adults.

Methods: This population-based cross-sectional study included 184 rural-dwelling adults (age ≥65 years, 39.1% women) in Shandong, China. In 2014-2016, we collected data on demographics, lifestyles, health conditions, and serum lipids. Volumes of gray matter, white matter, ventricle, hippocampus, and white matter hyperintensity were automatically estimated on brain MRI. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and mild cognitive impairment (MCI) was defined according to the Petersen's criteria. Data were analyzed using the general linear regression, logistic regression, and mediation models.

Results: Of the 184 participants, 47 were defined with MCI. Low HDL-C (<1.55 vs. ≥1.55 mmol/L) was significantly associated with reduced volumes of total white matter (multi-adjusted β=-9.77, 95% CI: -19.48--0.06) and hippocampus (-0.23, -0.46--0.01), a lower MMSE score (-1.49, -2.67--0.31), and a higher likelihood of MCI (multi-adjusted odds ratio=3.21, 95% CI: 1.42-7.29). The mediation effects of structural brain measures on the associations between a low level of HDL-C and MMSE score or MCI were not statistically significant (P>0.05).

Conclusions: This study suggests that low HDL-C may be involved in structural brain aging and cognitive dysfunction among rural-dwelling older adults in China, but the association of low HDL-C with cognitive aging phenotypes appears not to be mediated by brain structure.
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http://dx.doi.org/10.1111/ene.14939DOI Listing
May 2021

Refractory Kawasaki disease: modified methylprednisolone regimen decreases coronary artery dilatation.

Pediatr Res 2021 May 21. Epub 2021 May 21.

Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.

Background: The use of corticosteroids in Kawasaki disease (KD) is still controversial. The aim of this study was to investigate the safety and effectiveness of modified methylprednisolone (mPSL) regimen as an initial treatment for refractory KD.

Methods: This is a real-world observational study. We identified refractory KD with a self-developed scoring system. Patients were divided into the intravenous immunoglobulin (IVIG) + mPSL group and the IVIG group. Clinical outcomes and changes in coronary arteries after the treatment during a 12-week period were observed. Propensity-score matching was used to analyze those patients with similar baseline characteristics.

Results: Of a total of 168 patients, 104 patients were assigned into the IVIG group and 64 patients into the IVIG + mPSL group. The therapeutic response rate of the IVIG + mPSL group was significantly higher than that of the IVIG group (98.4 vs 76.0%, P < 0.05). The IVIG + mPSL group had a shorter duration of fever and a higher rate of C-reactive protein decline than the IVIG group (1.17 ± 0.64 vs 1.81 ± 1.16 days; 88.1 vs 83.5%; P < 0.05). The luminal diameter and Z-score of the left circumflex coronary artery (LCX) were significantly smaller and lower in the IVIG + mPSL group than that in the IVIG group at weeks 2 and 12.

Conclusions: Modified mPSL regimen has minimal side effects. It might improve the initial response to IVIG and decrease the dilation of LCX for refractory KD.

Impact: Modified mPSL regimen (2-4 mg/kg/day, divided into 2-3 doses for 3-5 days, then 1 mg/kg/day, once a day for 3-5 days, then oral prednisone was tapered over 3-5 weeks in 5-7 days steps) as an intensive initial treatment can decrease LCX dilation in high-risk IVIG-resistant KD patients. Our self-developed scoring system has been proven validated and can be used to identify high-risk IVIG-resistant KD patients in North China. The present study provides an alternative therapeutic regimen for high-risk refractory KD patients.
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http://dx.doi.org/10.1038/s41390-021-01576-6DOI Listing
May 2021

Proteomic Analysis Revealed the Characteristics of Key Proteins Involved in the Regulation of Inflammatory Response, Leukocyte Transendothelial Migration, Phagocytosis, and Immune Process during Early Lung Blast Injury.

Oxid Med Cell Longev 2021 27;2021:8899274. Epub 2021 Apr 27.

Shenyang Medical College, No. 146, Huanghe North Street, Shenyang 110034, China.

Previous studies found that blast injury caused a significant increased expression of interleukin-1, IL-6, and tumor necrosis factor, a significant decrease in the expression of IL-10, an increase in Evans blue leakage, and a significant increase in inflammatory cell infiltration in the lungs. However, the molecular characteristics of lung injury at different time points after blast exposure have not yet been reported. Therefore, in this study, tandem mass spectrometry (TMT) quantitative proteomics and bioinformatics analysis were used for the first time to gain a deeper understanding of the molecular mechanism of lung blast injury at different time points. Forty-eight male C57BL/6 mice were randomly divided into six groups: control, 12 h, 24 h, 48 h, 72 h, and 1 w after low-intensity blast exposure. TMT quantitative proteomics and bioinformatics analysis were performed to analyze protein expression profiling in the lungs from control and blast-exposed mice, and differential protein expression was verified by Western blotting. The results demonstrated that blast exposure induced severe lung injury, leukocyte infiltration, and the production of inflammatory factors in mice. After analyzing the expression changes in global proteins and inflammation-related proteomes after blast exposure, the results showed that a total of 6861 global proteins and 608 differentially expressed proteins were identified, of which 215, 128, 187, 232, and 65 proteins were identified at 12 h, 24 h, 48 h, 72 h, and 1 week after blast exposure, respectively. Moreover, blast exposure-induced 177 differentially expressed proteins were associated with inflammatory responses, which were enriched in the inflammatory response regulation, leukocyte transendothelial migration, phagocytosis, and immune response. Therefore, blast exposure may induce early inflammatory response of lung tissue by regulating the expression of key proteins in the inflammatory process, suggesting that early inflammatory response may be the initiating factor of lung blast injury. These data can provide potential therapeutic candidates or approaches for the development of future treatment of lung blast injury.
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http://dx.doi.org/10.1155/2021/8899274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099533PMC
April 2021

Molecular mechanism of protein dynamic change for Hengshan goat meat during freezing storage based on high-throughput proteomics.

Food Res Int 2021 May 9;143:110289. Epub 2021 Mar 9.

School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.

As traditional frozen storage leads to the degradation of meat quality, elucidation of dynamic change mechanism is urgently needed. Proteomic differences in postmortem frozen storage time (0, 30 and 60 days) of Hengshan goat meat at -18 °C were studied by label-free proteomics based on high resolution quadrupole-Orbitrap mass spectrometry. A total of 492 proteins were identified, of which 485 proteins were quantified, and the difference of 199 proteins was observed. The analysis of the differentially expressed proteins related to quality observed that triosephosphate isomerase and peroxiredoxin-6 were potential biomarkers for goat meat discoloration. Troponin and myosin can represent the tenderness of goat meat. Heat shock protein 70 can be used as water-retaining proteins in goat meat. Bioinformatics analysis suggested that the distinguishingly expressed proteins were involved in glycolysis and the ubiquitin-proteasome pathway revealing that the strong degradation of proteins, which cause of the degradation of long-term frozen meat quality. These results could enrich and beyond the existing knowledge of frozen meat, expecting to have a further understanding of the changes of meat quality at the molecular level.
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http://dx.doi.org/10.1016/j.foodres.2021.110289DOI Listing
May 2021

circSnx12 Is Involved in Ferroptosis During Heart Failure by Targeting miR-224-5p.

Front Cardiovasc Med 2021 21;8:656093. Epub 2021 Apr 21.

Laboratory of Rescue Center of Severe Wound and Trauma Chinese People's Liberation Army, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command of China Medical University, Shenyang, China.

Circular RNA (circRNA) is a subclass of non-coding RNAs that enables the circular transcripts resistant to the exonuclease digestion. Iron homeostasis is essential for the body to maintain normal physiological functions. At present, the relationship among circRNA, iron metabolism and heart failure remains largely unknown. This study aimed to explore the regulatory mechanism of circRNA and iron metabolism in heart failure. We obtained circRNA, miRNA and mRNA data from public databases and built a ceRNA network. The prediction results were verified in the myocardial tissues of pressure overload-induced heart failure mice through the use of histopathological staining methods, iron and malondialdehyde (MDA) measurement tests, quantitative real-time PCR (qRT-PCR), Western blot analysis and luciferase reporter assay. A total of 4 genes related to iron metabolism and oxidative stress were identified, and a ceRNA network involving 7 circRNAs, 7 miRNAs, and 4 mRNAs was constructed using bioinformatics tools. The results of qRT-PCR and Western blot analyses indicated that the expression level of FTH1 was similar with that predicted by bioinformatics analysis. Echocardiographic measurement showed that heart failure mice have lower fractional shortening and ejection fraction. Moreover, the myocardium of heart failure mice displayed obvious fibrosis as well as increased levels of iron and MDA compared to control mice. Besides, circSnx12 could act as an endogenous sponge to bind with miR-224-5p, and the 3'UTR region of FTH1 also had miRNA binding sites. A circRNA-miRNA-mRNA regulatory network was successfully constructed by identifying differentially expressed genes related to iron metabolism. This new approach reveals potential circRNA targets for the treatment of heart failure.
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http://dx.doi.org/10.3389/fcvm.2021.656093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097164PMC
April 2021

Automated detection of hippocampal sclerosis: Comparison of a composite MRI-based index with conventional MRI measures.

Epilepsy Res 2021 Aug 9;174:106638. Epub 2021 Apr 9.

Department of Radiology, Sanbo Brain Hospital, Capital Medical University, China. Electronic address:

Purpose: This study aims to compare the performance of an MRI-based composite index (HSI) with conventional MRI-based measures in hippocampal sclerosis (HS) detection and postoperative outcome estimation.

Methods: Seventy-two temporal lobe epilepsy (TLE) patients with pathologically confirmed HS and fifteen TLE patients without HS were included retrospectively. The T1-weighted and FLAIR images of these patients were processed with AccuBrain to quantify the hippocampal volume (HV) and the hippocampal FLAIR signal. The HSI index that considered both HV and hippocampal FLAIR signal was also calculated. Two experienced neuropathologists rated the HS severity with the resected tissue and reached an agreement for all cases. The asymmetry indices of the MRI measures were used to lateralize the sclerotic side, and the original MRI measures were applied to detect HS vs. normal hippocampi. Operating characteristic curve (ROC) analyses were performed for these predictions. We also investigated the sensitivity of the ipsilateral MRI measures in characterizing the pathological severity of HS and the associations of the MRI measures with postoperative outcomes (Engel class categories).

Results: With the optimal cutoffs, the asymmetry indices of HSI and HV both achieved excellent performance in differentiating left vs. right HS (accuracy = 100 %), and the absolute value of the asymmetry index of HSI performed best in differentiating unilateral vs. bilateral HS (accuracy = 91.7 %). Regarding the detection of HS, HSI performed better in sensitivity (94.4 % vs. 87.5 %) while HV performed better in specificity (93.6 % vs. 89.4 %) when the contralateral site of unilateral HS and both sides of non-HS patients were considered as the normal reference, and HSI performed even better than HV when only both sides of non-HS patients were considered as the normal reference (AUC: 0.956 vs. 0.934, p = 0.038). The ipsilateral HSI presented the strongest association with the pathological rating of HS severity (r = 0.405, p < 0.001). None of the ipsilateral or contralateral MRI measures was associated with the postoperative outcomes. Among the asymmetry indices, only the absolute value of the asymmetry index of HV presented a significant association with the Engel classifications for the Year 2∼3 visit (r = -0.466, p = 0.004) or the latest visit with >1 year follow-up (r = -0.374, p = 0.003) while controlling for disease duration and follow-up duration.

Conclusion: The HSI index and HV presented comparable good performance in HS detection, and HSI may have better sensitivity than HV in differentiating pathological HS severity. Higher magnitude of HV dissymmetry may indicate better post-surgical outcomes for HS patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106638DOI Listing
August 2021

Emission factors of environmentally persistent free radicals in PM from rural residential solid fuels combusted in a traditional stove.

Sci Total Environ 2021 Jun 6;773:145151. Epub 2021 Feb 6.

Stockbridge School of Agriculture, University of Massachusetts, Amherst, MA 01003, United States.

Emission factors (EFs) are crucial for establishing emission inventory and subsequent health risk assessment of pollutants. However, the EFs of environmentally persistent free radicals (EPFRs) in PM have not been well investigated. We measured EPFRs in PM from burning of different solid fuels in a traditional stove widely used in rural China and calculated the EFs of EPFRs (EF). The characteristics of EPFRs varied greatly with PM depending on the feedstock, and the EF of crop residue, firewood and bitumite was 2.13 ± 1.04, 1.40 ± 0.76 and 1.08 ± 0.39 (10 spins·kg), respectively. The estimated results of EPFRs emission associated with PM showed that the crop residue was the main contributor to the top four provinces with high EPFRs emissions in China in 2010. A wide range (0.03-4.89 cig·person·day) of equivalent cigarette number converted by inhaling EPFRs in PM was observed. Provinces with higher equivalent cigarette number were mainly agricultural provinces, because the rural residents tend to use readily available fuels. Additionally, EPFRs in collected PM during 2 - month photoaging were more stable in particles with higher organic carbon contents. Our findings provided a new insight into the risk assessment of PM from different sources by taking EPFRs into consideration.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145151DOI Listing
June 2021

Autophagy induction in tumor surrounding cells promotes tumor growth in adult Drosophila intestines.

Dev Biol 2021 Aug 1;476:294-307. Epub 2021 May 1.

College of Life Sciences, Capital Normal University, Beijing, 100048, China. Electronic address:

During tumorigenesis, tumor cells interact intimately with their surrounding cells (microenvironment) for their growth and progression. However, the roles of tumor microenvironment in tumor development and progression are not fully understood. Here, using an established benign tumor model in adult Drosophila intestines, we find that non-cell autonomous autophagy (NAA) is induced in tumor surrounding neighbor cells. Tumor growth can be significantly suppressed by genetic ablation of autophagy induction in tumor neighboring cells, indicating that tumor neighboring cells act as tumor microenvironment to promote tumor growth. Autophagy in tumor neighboring cells is induced downstream of elevated ROS and activated JNK signaling in tumor cells. Interestingly, we find that active transport of nutrients, such as amino acids, from tumor neighboring cells sustains tumor growth, and increasing nutrient availability could significantly restore tumor growth. Together, these data demonstrate that tumor cells take advantage of their surrounding normal neighbor cells as nutrient sources through NAA to meet their high metabolic demand for growth and progression. Thus we provide insights into our understanding of the mechanisms underlying the interaction between tumor cells and their microenvironment in tumor development.
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http://dx.doi.org/10.1016/j.ydbio.2021.04.008DOI Listing
August 2021

Fast hypothermia induced by extracorporeal circuit cooling alleviates renal and intestinal injury after cardiac arrest in swine.

Am J Emerg Med 2021 Apr 23;47:231-238. Epub 2021 Apr 23.

Hangzhou Emergency Medical Center of Zhejiang Province, Zhejiang, Hangzhou, China. Electronic address:

Background: Continuous renal replacement therapy (CRRT) was currently demonstrated to be an effective way to induce fast hypothermia and had proective effects on cardiac dysfunction and brain damage after cardiac pulmonary resuscitation (CPR). In the present study, we aimed to investigate the influence of extracorporeal circuit cooling using CRRT on renal and intestinal damage after CPR based on a porcine model.

Methods: 32 pigs were subjected to ventricular fibrillation for 8 min, followed by CPR for 5 min before defibrillation. All were randomized to receive extracorporeal circuit cooling using CRRT (CRRT, n = 9), surface cooling (SC, n = 9), normothermia (NT, n = 9) or sham control (n = 5) at 5 min post resuscitation. Pigs in the CRRT group were cooled by 8-h CRRT cooling with the infusion line initially submerged in 4 °C of ice water and 16-h SC, while in the SC group by a 24-h SC. Temperatures were maintained at a normal range in the other two groups. Biomarkers in serum were measured at baseline and 1, 3, 6, 12, 24 and 30 h post resuscitation to assess organ functions. Additionally, tissues of kidney and intestine were harvested, from which the degree of tissue inflammation, oxidative stress, and apoptosis levels were analyzed.

Results: The blood temperature decreased faster by extracorporeal circuit cooling using CRRT than SC (9.8 ± 1.6 vs. 1.5 ± 0.4 °C/h, P < 0.01). Post-resuscitation renal and intestinal injury were significantly improved in the 2 hypothermic groups compared to the NT group. And the improvement was significantly greater in animals received extracorporeal circuit cooling than those received surface cooling, from both the results of biomarkers in serum and pathological evidence.

Conclusion: Fast hypothermia induced by extracorporeal circuit cooling was superior to. surface cooling in mitigating renal and intestinal injury post resuscitation.
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http://dx.doi.org/10.1016/j.ajem.2021.04.057DOI Listing
April 2021

Controllable high-performance memristors based on 2D FeGeTeoxide for biological synapse imitation.

Nanotechnology 2021 May 19;32(32). Epub 2021 May 19.

College of Information Science and Electronic Engineering, Hangzhou 310027, People's Republic of China.

Memristors are an important component of the next-generation artificial neural network, high computing systems, etc. In the past, two-dimensional materials based memristors have achieved a high performance and low power consumption, though one at the cost of the other. Furthermore, their performance can not be modulated frequently once their structures are fixed, which remains the bottleneck in the development. Herein, a series of forming free memristors are fabricated with the same Cu/FeGeTeoxide/FeGeTe/Al structure, yet the On/Off ratio and set voltage is modulated continuously by varying the oxidation time during fabrication. With an optimal oxidation time, a large On/Off ratio (1.58 × 10) and low set voltage (0.74 V) is achieved in a single device. The formation and rapture of Al conductive filaments are found to be responsible for the memristors, and the filaments density and the cross-section area increase with the increase of current compliance, which achieves a higher On/Off ratio. The memristor can imitate basic biological synaptic functions using voltage pulses, demonstrating the potential for low-power consuming neuromorphic computing applications.
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http://dx.doi.org/10.1088/1361-6528/abfd58DOI Listing
May 2021

Dynamic changes and multiplication rate of white blood cell count may direct the timing of cytoreduction chemotherapy during induction treatment in newly diagnosed acute promyelocytic leukemia with low-intermediate risk.

Mol Clin Oncol 2021 Jun 5;14(6):112. Epub 2021 Apr 5.

Department of Hematology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621000, P.R. China.

In order to explore the optimal timing for initiating cytoreduction chemotherapy following all-trans retinoic acid plus arsenic trioxide administration, 58 newly diagnosed patients with acute promyelocytic leukemia (APL) with low-intermediate mortality risk were retrospectively analyzed. During induction treatment, white blood cell (WBC) count >4x10/l and multiplication rate of WBC <3 days were defined as rapid WBC multiplication. Patients were divided into two groups: With or without rapid WBC multiplication. Comparison between the two groups revealed that the incidence of differentiation syndrome (DS) (48.1% vs. 6.5%; P<0.001), grade 3-4 bleeding (34.8% vs. 6.5%; P=0.022) and peak WBC count (30.4±20.0x10/l vs. 8.67±5.4x10/l; P<0.001) were significantly higher in the group with rapid WBC multiplication compared with in the group without rapid WBC multiplication. No significant differences were observed in bone marrow depression, infection, complete remission (CR) rate, time to achieve CR and early mortality rate between the two groups. Multivariate analysis revealed that WBC count at chemotherapy initiation was an independent risk factor for the occurrence of DS (P=0.040). Peak WBC count and rapid WBC multiplication were significantly associated with grade 3-4 bleeding (P=0.019 and P=0.002, respectively). Hence, WBC count at chemotherapy initiation along with its multiplication rate may direct the timing of cytoreduction chemotherapy during induction treatment in newly diagnosed APL with low-intermediate risk.
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http://dx.doi.org/10.3892/mco.2021.2274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060852PMC
June 2021

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

Lancet Neurol 2021 06 23;20(6):448-459. Epub 2021 Apr 23.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.

Methods: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.

Findings: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high.

Interpretation: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.

Funding: The Netherlands Organisation for Health Research and Development.
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http://dx.doi.org/10.1016/S1474-4422(21)00060-0DOI Listing
June 2021

High-Coverage Screening of Sulfonamide Metabolites in Goat Milk by Magnetic Doped S Graphene Combined with Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry.

J Agric Food Chem 2021 Apr 16;69(16):4755-4765. Epub 2021 Apr 16.

School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.

Currently, there are more than 1000 varieties of synthetic sulfonamides universally used as antibiotics causing severe results of potential carcinogenicity and drug resistance for human health due to excessive residue of animal-derived food. A facile and novel approach for untargeted screening of sulfonamides (SAs) and metabolites was proposed based on magnetic solid-phase extraction-ultrahigh-performance liquid chromatography-tandem high-resolution mass spectrometry (MSPE-UHPLC-HRMS). Compared with QuEChERS without the clean-up procedure and SPE in terms of matrix effect and absolute recovery, magnetic doped S graphene (S-doping level: 2.82%) synthesized via a solid-state microwave approach and the aggregation wrap mechanism was used as a novel adsorbent for nonspecific extraction of desired analytes by the noncovalent interaction between electron-deficient thiophene sulfur and electron donors such as amino or amide as well as π-π stacking interactions. Combined with variable data-independent acquisition, characteristic fragment-ion filtering ( 156.01138 or 108.04439) and assignment of extracted-ion chromatograms of marked fragment ions were successfully utilized to screen the desired analytes and subsequently confirmed with the availability of reference standards. The optimized and validated approach for spiked 26 SAs and 9 metabolites in control goat milk demonstrated satisfactory accuracy (80.1-112.6%) and precision (RSDs < 6.4%) for matrix-matched standard addition. After applying suspect goat milk samples, untargeted SA analytes including sulfanilamide or an N-acetylsulfamethazine metabolite with concentration ranging from 66.3 to 398.5 ng L were determined in 5 of 45 goat milk samples.
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http://dx.doi.org/10.1021/acs.jafc.1c01431DOI Listing
April 2021

Swimming Exercise Ameliorates Hypertension-Induced Kidney Dysfunction via Alleviating Renal Interstitial Fibrosis and Apoptosis.

Kidney Blood Press Res 2021 13;46(2):219-228. Epub 2021 Apr 13.

School of Physical Education, Shaanxi Normal University, Xi'an, China.

Background: Hypertensive nephropathy is one of the major causes of ESRD. Exercise has been considered a nonpathological therapy for hypertension and its complications, yet mechanisms remain unclear. We sought to investigate whether periodic swimming could ameliorate hypertension-induced kidney dysfunction and its underlying mechanisms.

Methods: Four-week male spontaneously hypertensive rats (SHRs) were randomly divided into the hypertension group (SHR, n = 8) and exercise group (SE, n = 8, 60 min swimming/day, 6 days per week, for 8 weeks). Wistar-Kyoto rats (WKY, n = 8) were served as a sedentary normotensive group. Bodyweight and blood pressure (BP) were recorded weekly. After 8-week sedentary or swimming exercise, lipids profile, BUN, and Cr were measured. The renal interstitial fibrosis was examined by the histopathological analysis using Masson's trichrome staining and hematoxylin and eosin staining. The kidney cell apoptosis was tested by TUNEL staining. The expressions of critical proteins responsible for the TGF-β1/Smad signaling of fibrosis, that is, TGF-β1, Smad2/3, and Smad7, as well as apoptosis related proteins, Bax and Bcl-2 in kidney cortex tissues were measured.

Results: The 8-week swimming exercise reduced BP and bodyweight, lowered concentrations of BUN, and serum Cr, compared with SHR. Exercise remarkably inhibited hypertension-induced tubular degeneration, cellular cluster, and tubular cell swelling as well as glomerular degeneration in the kidney cortical tissues, attenuated renal interstitial fibrosis, and renal cell apoptosis. Moreover, expressions of TGF-β1, Smad2/3, and Bax were higher in the SHR than the WKY, which were significantly suppressed by the exercise. In contrast, hypertension-reduced expressions of Smad7 and Bcl-2 were enhanced by the swimming exercise. Strong correlations were found between kidney function indices, blood lipids, and key protein expressions.

Conclusion: Our results demonstrate beneficial effects of the periodic swimming on ameliorating hypertension-induced kidney dysfunction highlighting the potential of swimming exercise as a nonpathological therapy for early prevention of hypertension-caused kidney diseases.
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http://dx.doi.org/10.1159/000514680DOI Listing
April 2021

O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity.

J Cell Physiol 2021 Apr 12. Epub 2021 Apr 12.

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.

O-GlcNAcylation is a posttranslational modification that regulates numerous nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes, such as transcription, signal transduction, and cell motility. Although increasing evidence has shown that elevated levels of global O-GlcNAcylation are linked to the metastasis in hepatocellular carcinoma (HCC) cells, the underlying mechanism is still ambiguous. In this study, we demonstrated that forkhead box protein A2 (FOXA2), an essential transcription factor for liver homeostasis and HCC developing, was O-GlcNAcylated by O-GlcNAc transferase (OGT) and regulates HCC cells migration and invasion. Opposite FOXA2 and OGT expression tendency were observed in HCC tissues, and lower FOXA2 levels predicted a poor prognosis in HCC patients. The reduction of FOXA2 in HCC cells was found to be inversely correlated with the cellular O-GlcNAcylation and cell migratory ability. Notably, we found that FOXA2 was modified by O-GlcNAcylation and that O-GlcNAcylation activated the ubiquitination degradation of FOXA2 in highly metastatic HCC cells. Although this modification did not affect FOXA2 nuclear localization capability, O-GlcNAcylation on FOXA2 was key for attenuating FOXA2-mediated transcription. O-GlcNAcylation decreased the transcription of FOXA2 downstream target gene E-cadherin and it ultimately promoted O-GlcNAcylation-mediated HCC cell migration and invasion. The results provide insights into the role of O-GlcNAcylation in regulating FOXA2 activity and suggest its important implications in HCC metastasis.
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http://dx.doi.org/10.1002/jcp.30385DOI Listing
April 2021

[CLAG Regimen Composed of Continuous Intravenous Infusion of Cladribine in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Apr;29(2):333-338

Henan Cancer Hospital/The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henna Province, China,E-mail:

Objective: To study the efficacy and safety of continuous intravenous infusion of 2-Chlorodeoxyadenosine (2-CdA) combined with high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF) (CLAG regiem) in the treatment of relapsed/refractory acute myeloid leukemia (AML).

Methods: Fifteen patients with refractory/relapsed AML hospitalized in 5 medical units such as Department of Hematology, the Affiliated Tumor Hospital of Zhengzhou University and received one course of CLAG regimen from June 2014 to August 2019 were analyzed retrospectively (specifically: cladribine 5 mg/M, day 1 to day 5, continuous 24-hour intravenous infusion; Ara-C 2 g/M, 1 time/day, day 1 to day 5, intravenous infusion; G-CSF 300 mg, 1 time/day, day 0 to day 5, subcutaneous injection).

Results: Among the 15 patients with refractory/relapsed AML, 9 males and 6 females, the median age was 35 (13-63) years old. FAB classification: 1 case of M, 3 cases of M, 4 cases of M (including 1 case with extramedullary invasion), 1 case of M4 with extramedullary invasion, 5 cases of M5, 1 case of HAL; NCCN classification: 6 cases in intermediate risk group, 9 cases in high risk group; 8 cases refractory, 7 cases relapsed. The median time of pre-chemotherapy was 4 (2-8) (of which NO.15 had received 8 cycles of chemotherapy and received CLL1-CAR-T), and the median white blood cell count before chemotherapy was 12.27 (from 0.78 to 5.29)×109/L. After 1 course of treatment with CLAG regimen, 12 patients achieved complete remission (12/15, 80%), and the median duration of CR was 65 days (0-528) days. IV grade leukopenia and thrombocytopenia was found in all the patients after chemotherapy. The median duration of granulocytosis was 20 (14 to 33) days, and 1 patient died. Seven patients received allogeneic hematopoietic stem cell transplantation. The median EFS and OS time of 15 patients was 85 (19-558) days and 117 (19-558) days, respectively.

Conclusion: The CLAG regimen consisting of continuous intravenous infusion of cladribine shows high CR in the treatment of AML patients, but the duration of CR is short, myelosuppression is sever, so that infection control is the key. Allogeneic hematopoietic stem cells transplantation should be performed as soon as possible after CR.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.02.005DOI Listing
April 2021

Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial.

Ann Rheum Dis 2021 Apr 2. Epub 2021 Apr 2.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Objective: To evaluate the effects of denosumab on erosion healing at 2-4 metacarpophalangeal (MCP) head as determined by high-resolution peripheral quantitative CT (HR-pQCT) in patients with rheumatoid arthritis (RA) with stable disease.

Methods: This was a randomised, placebo-controlled, double-blind study. Patients with RA with disease activity score 28 joints (DAS28) ≤5.1 were randomised (1:1) to subcutaneous denosumab 60 mg or placebo once every 6 months for 24 months. The primary outcome was erosion healing at MCP 2-4 on HR-pQCT at 12 months. The effects of denosumab on erosion and joint space parameters on HR-pQCT and radiographs, disease activity and health assessment questionnaire-disability index (HAQ-DI) were also examined.

Results: At 24 months, HR-pQCT images were analysed in 98 patients. One-third of the patients achieved sustained low disease activity throughout the study. At 12 months, changes in erosion parameters on HR-pQCT were similar between the two groups. At 24 months, new erosions (19% vs 9%, p=0.009) and erosion progression (18% vs 8%, p=0.019) were more common in the placebo group than the denosumab group. Erosion healing was seen in a significantly higher proportion of patients in the denosumab group (20% vs 6%, p=0.045) at 24 months. No significant changes in joint space parameters on HR-pQCT, van der Heijde-Sharp erosion score, DAS28 and HAQ-DI were observed in the two groups at 12 and 24 months.

Conclusion: Although no differences in erosion parameters were observed at 12 months, denosumab was more efficacious than placebo in erosion repair on HR-pQCT after 24 months.

Trial Registration Number: NCT03239080.
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http://dx.doi.org/10.1136/annrheumdis-2021-219846DOI Listing
April 2021

A Genetic Model Reveals Biological Features of Neonatal CD4 Helper Cells Undergone Homeostasis in Mice.

Front Cell Dev Biol 2021 11;9:659744. Epub 2021 Mar 11.

Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.

CD4 T cells are essential for regulating effective immune response to pathogens and immune balance. Recent studies have demonstrated the unique features of T cells in neonate mice, such as more sensitive to antigen response and preference toward T helper 2 (Th2) response and regulatory T cells (Tregs) differentiation. However, the biological characteristics of neonatal age-derived CD4 T cells following homeostasis remain unclear. Here we utilized a lineage tracing model of δ to mark neonatal- and adult-derived CD4 T cells followed by a combination analysis of activation, proliferation, survival, and differentiation. Our results showed that neonatal CD4 T cells had higher capacity of activation, proliferation, apoptosis, and differentiation toward Th2 and T helper 17 (Th17) lineages, accompanied by a reduced potential for T helper 1 (Th1), T helper 9 (Th9), and Treg lineages. In contrast, tracked neonatal CD4 T cells exhibited similar characters of above-mentioned of tracked adult cells in adult mice. Therefore, our data support a natural requirement for CD4 T cells to acquire fully-equipped functional potentials of adult cells.
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http://dx.doi.org/10.3389/fcell.2021.659744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991801PMC
March 2021

Prenatal Hypoxia Altered Angiotensin II-mediated Vasoconstrictions PKC/ERK/ROCK Pathways and Potassium Channels in Rat Offsrping Middle Cerebral Artery.

Biomed Environ Sci 2021 Mar;34(3):250-255

Reproductive Medicine Center, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China.

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http://dx.doi.org/10.3967/bes2021.033DOI Listing
March 2021

Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21.

Redox Biol 2021 May 11;41:101940. Epub 2021 Mar 11.

Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China. Electronic address:

Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain MDA level in aged mice hippocampi. Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels. Recombinant FGF21 treatment balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2 in SH-SY5Y cells. Moreover, knockdown of Fgf21 by i.v. injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice. In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.
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http://dx.doi.org/10.1016/j.redox.2021.101940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022247PMC
May 2021