Publications by authors named "Junling Liu"

154 Publications

LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.

Cell Rep 2021 Nov;37(8):110038

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China. Electronic address:

Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
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http://dx.doi.org/10.1016/j.celrep.2021.110038DOI Listing
November 2021

Vps33B in Dendritic Cells Regulates House Dust Mite-Induced Allergic Lung Inflammation.

J Immunol 2021 12 3;207(11):2649-2659. Epub 2021 Nov 3.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China;

Dendritic cells (DCs) are the most specialized APCs that play a critical role in driving Th2 differentiation, but the mechanism is not fully understood. Here we show that vacuolar protein sorting 33B (Vps33B) plays an important role in this process. Mice with -specific deletion in DCs, but not in macrophages or T cells, were more susceptible to Th2-mediated allergic lung inflammation than wild-type mice. Deletion of Vps33B in DCs led to enhanced CD4 T cell proliferation and Th2 differentiation. Moreover, Vps33B specifically restrained reactive oxygen species production in conventional DC1s to inhibit Th2 responses in vitro, whereas Vps33B in monocyte-derived DCs and conventional DC2s was dispensable for Th2 development in asthma pathogenesis. Taken together, our results identify Vps33B as an important molecule that mediates the cross-talk between DCs and CD4 T cells to further regulate allergic asthma pathogenesis.
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http://dx.doi.org/10.4049/jimmunol.2100502DOI Listing
December 2021

SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury.

Cell Discov 2021 Oct 12;7(1):93. Epub 2021 Oct 12.

Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation-deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.
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http://dx.doi.org/10.1038/s41421-021-00326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511299PMC
October 2021

The binding of autotaxin to integrins mediates hyperhomocysteinemia-potentiated platelet activation and thrombosis.

Blood Adv 2021 Sep 24. Epub 2021 Sep 24.

Peking University, Beijing, China.

Hyperhomocysteinemia (HHcy) is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Here, a human medical examination report showed that elevated human plasma Hcy levels were positively correlated with enhanced blood coagulation and platelet activity, suggesting that humans with HHcy are more prone to thrombus formation at the sites of vascular injury. Accordingly, we observed accelerated platelet activation, primary hemostasis, and thrombus formation both in acute and chronic HHcy ApoE-/- mice. Upon Hcy administration in C57BL/6J mice, platelet aggregation, spreading, and clot retraction were markedly promoted. More importantly, homocysteine (Hcy) increased the affinity of platelet integrin αIIbβ3 with ligands and enhanced integrin outside-in signaling by promoting membrane phosphatidylserine (PS) exposure in vitro. Mechanistically, lipidomics analysis showed that lysophosphatidylcholines were the primary metabolites leading to clustering of HHcy-stimulated platelets. Cytosolic phospholipase A2 (cPLA2) activity and autotaxin (ATX, a secreted lysophospholipase D) secretion were upregulated by Hcy, leading to membrane phospholipid hydrolysis and PS exposure. Moreover, secreted ATX directly interacted with integrin β3. Inhibitors of cPLA2 and ATX activity blocked integrin αIIbβ3 outside-in signaling and thrombosis in HHcy ApoE-/- mice. This study identifies a novel mechanism by which HHcy promotes platelet membrane phospholipid catabolism and extracellular ATX secretion to activate integrin outside-in signaling, consequently to exaggerate thrombosis. This study reveals an innovative approach to treat HHcy-related thrombotic diseases.
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http://dx.doi.org/10.1182/bloodadvances.2021004572DOI Listing
September 2021

Bentazone in water and human urine in Wuhan, central China: exposure assessment.

Environ Sci Pollut Res Int 2021 Aug 31. Epub 2021 Aug 31.

Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.

Bentazone is a widely used post-emergence herbicide, while no data was available on its concentrations in tap water from China and in urine among the general population. It was determined in the source (Wuhan section of the Yangtze River watershed), treated, and tap water (n = 20, 20, and 170, respectively) in different seasons (2019) in Wuhan, central China. Also, urine samples (n = 38) collected from healthy adults in Wuhan (September 2020) were analyzed to characterize its urinary concentration. Bentazone was detected in all the source and treated water samples. Its concentrations in the source water in July were higher than those in February (median: 17.9 ng/L vs. 2.86 ng/L) (p < 0.05). It cannot be removed efficiently (27.8-27.9%) by conventional drinking water treatment using NaClO, but it can be efficiently removed by using chlorine dioxide or ozone combined with activated carbon. Bentazone was frequently detected (detection frequency: 96.3%) in 160 tap water samples (underwent conventional treatment) (median: 1.95 ng/L, range: <0.02-47.0 ng/L), while it was not detectable in tap water samples that underwent ozone combined with activated carbon. Seasonal variations were found, with the lowest median concentration (ng/L) in April (0.46) and the highest in July (17.6). In addition, bentazone was frequently (92.1%) detected in human urine samples (median: 0.02 ng/mL; range: < 0.01-0.11 ng/mL). The estimated daily intake of bentazone based on its median concentration in tap water (0.04 ng/kg-body weight [bw]/day) accounted for approximately 8% of that based on the median urinary concentration (0.48 ng/kg-bw/day). This is the first time to characterize its occurrence in drinking water from China and its occurrence in the urine of the general population.
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http://dx.doi.org/10.1007/s11356-021-16177-3DOI Listing
August 2021

Chemoprotective Effect of Daphnetin Against Benzene-induced Leukemia via Alteration of CYP2E1.

Appl Biochem Biotechnol 2021 Aug 24. Epub 2021 Aug 24.

Department of Hematology, Qingdao Hiser Medical Center, Shibei District, No. 4 Renmin Road, Qingdao City, 266033, Shandong Province, China.

Leukemia is the overproduction of a large number of immature blood cells entering into the peripheral blood due to the malignancy of blood-forming tissues. The modern treatment mechanisms that are associated with leukemia comprise chemotherapy, allogeneic cell transplantation, and radiation therapy that comes with adverse side effects. Thus, medicinal herbs and their bioactive compounds are gaining more attention nowadays toward the treatment of leukemia, owing to their minimal side effects. The current study was aimed to scrutinize the antileukemic effect of daphnetin against benzene-induced leukemia in rats and explore the underlying mechanism of its action. Benzene was used for the induction of leukemia in experimental rats. The rats were divided into different groups and body weight; hematological parameters, DNA fragmentation, and cell cycle regulatory parameter were also estimated. RT-PCR was used for the estimation of mRNA expression of cytochrome P450 2E1 (CYP2E1), a membrane protein widely found in liver cells. Daphnetin-treated rats showed upregulation of body weight as compared to other groups. Moreover, daphnetin reduced the blasts (67.8%) in leukemic rats. It also altered the hematological parameters such as RBC (69.8%), WBC (54.5%), lymphocytes (47.6%), neutrophils (48.9%), monocytes (44.7%), eosinophils (48.7%), and basophils (43.5%), respectively. Daphnetin-treated rats showed an increased level of proteins p21 and p53 and reduced level of cyclins D1 and E. RT-PCR showed an upregulated mRNA expression of CYP2E1 (48.4%) of the daphnetin-treated group as compared to other groups. The current study shows the antileukemic effect of daphnetin and highlights the possibility of its use in leukemia to minimize the side effect of the usual therapy.
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http://dx.doi.org/10.1007/s12010-021-03611-yDOI Listing
August 2021

Effect of hirudin on arterialized venous flap survival in rabbits.

Biomed Pharmacother 2021 Oct 4;142:111981. Epub 2021 Aug 4.

Department of Hand and Microsurgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; the Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China. Electronic address:

Arterialized venous flap (AVF) is limited in clinical application because its survival remains inconsistent and its exact survival mechanism is still unclear. Hirudin is an effective thrombin specific inhibitor, which is isolated from the salivary gland secretions of the leech. Our study evaluated the impact of hirudin on the viability of AVFs in rabbits. Thirty-six rabbits were randomly divided into three groups: sham group (physiological perfusion), control group (AVF), and hirudin group (AVF + hirudin). In hirudin group, 20 antithrombin units (ATU) hirudin (2.5 ml) were injected into each flap. In sham group and control group, the same amount of normal saline was injected into each flap. Status of flap survival, water content, vascular perfusion, histopathology, expression of CD34, VEGF, eNOS and HIF-1α were analyzed in each group. Analysis of oxidative stress was performed by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Compared with flaps in sham group with physiological perfusion mode, results of survival rate, perfusion status, SOD activity, expression of CD34, VEGF, and eNOS of AVFs in control group were significantly lower, while water content, MDA level and expression of HIF-1α were higher. The flap condition of AVFs injected with hirudin in hirudin group was improved significantly, and the results were similar to sham group. Our findings revealed that hirudin can effectively improve survival of AVF.
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http://dx.doi.org/10.1016/j.biopha.2021.111981DOI Listing
October 2021

Roxadustat Does Not Affect Platelet Production, Activation, and Thrombosis Formation.

Arterioscler Thromb Vasc Biol 2021 10 5;41(10):2523-2537. Epub 2021 Aug 5.

Department of Cardiology, Ruijin Hospital (J.Z., R.Z., X.Y.), Shanghai Jiao Tong University School of Medicine, China.

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function. Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice. Conclusions: Administration of roxadustat has no significant impact on platelet production and function.
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http://dx.doi.org/10.1161/ATVBAHA.121.316495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454499PMC
October 2021

NAC Transcription Factor PwNAC11 Activates by Interaction with ABF3 and DREB2A to Enhance Drought Tolerance in Transgenic .

Int J Mol Sci 2021 Jun 28;22(13). Epub 2021 Jun 28.

Key Laboratory of Forest Silviculture and Conservation of the Ministry of Education, The College of Forestry, Beijing Forestry University, Beijing 100083, China.

NAC (NAM, ATAF1/2, and CUC2) transcription factors are ubiquitously distributed in eukaryotes and play significant roles in stress response. However, the functional verifications of NACs in remain largely uncharacterized. Here, we identified the NAC transcription factor PwNAC11 as a mediator of drought stress, which was significantly upregulated in under drought and abscisic acid (ABA) treatments. Yeast two-hybrid assays showed that both the full length and C-terminal of PwNAC11 had transcriptional activation activity and PwNAC11 protein cannot form a homodimer by itself. Subcellular observation demonstrated that PwNAC11 protein was located in nucleus. The overexpression of in obviously improved the tolerance to drought stress but delayed flowering time under nonstress conditions. The steady-state level of antioxidant enzymes' activities and light energy conversion efficiency were significantly increased in PwNAC11 transgenic lines under dehydration compared to wild plants. transgenic lines showed hypersensitivity to ABA and PwNAC11 activated the expression of the downstream gene by binding to ABA-responsive elements (ABREs) instead of drought-responsive elements (DREs). Genetic evidence demonstrated that PwNAC11 physically interacted with an ABA-induced protein-ABRE Binding Factor3 (ABF3)-and promoted the activation of promoter, which implied an ABA-dependent signaling cascade controlled by PwNAC11. In addition, qRT-PCR and yeast assays showed that an ABA-independent gene-DREB2A-was also probably involved in PwNAC11-mediated drought stress response. Taken together, our results provide the evidence that PwNAC11 plays a dominant role in plants positively responding to early drought stress and ABF3 and DREB2A synergistically regulate the expression of .
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http://dx.doi.org/10.3390/ijms22136952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269012PMC
June 2021

Weighing features of lung and heart regions for thoracic disease classification.

BMC Med Imaging 2021 06 10;21(1):99. Epub 2021 Jun 10.

Department of Computer Science and Engineering, Southern University of Science and Technology, Shenzhen, China.

Background: Chest X-rays are the most commonly available and affordable radiological examination for screening thoracic diseases. According to the domain knowledge of screening chest X-rays, the pathological information usually lay on the lung and heart regions. However, it is costly to acquire region-level annotation in practice, and model training mainly relies on image-level class labels in a weakly supervised manner, which is highly challenging for computer-aided chest X-ray screening. To address this issue, some methods have been proposed recently to identify local regions containing pathological information, which is vital for thoracic disease classification. Inspired by this, we propose a novel deep learning framework to explore discriminative information from lung and heart regions.

Result: We design a feature extractor equipped with a multi-scale attention module to learn global attention maps from global images. To exploit disease-specific cues effectively, we locate lung and heart regions containing pathological information by a well-trained pixel-wise segmentation model to generate binarization masks. By introducing element-wise logical AND operator on the learned global attention maps and the binarization masks, we obtain local attention maps in which pixels are are 1 for lung and heart region and 0 for other regions. By zeroing features of non-lung and heart regions in attention maps, we can effectively exploit their disease-specific cues in lung and heart regions. Compared to existing methods fusing global and local features, we adopt feature weighting to avoid weakening visual cues unique to lung and heart regions. Our method with pixel-wise segmentation can help overcome the deviation of locating local regions. Evaluated by the benchmark split on the publicly available chest X-ray14 dataset, the comprehensive experiments show that our method achieves superior performance compared to the state-of-the-art methods.

Conclusion: We propose a novel deep framework for the multi-label classification of thoracic diseases in chest X-ray images. The proposed network aims to effectively exploit pathological regions containing the main cues for chest X-ray screening. Our proposed network has been used in clinic screening to assist the radiologists. Chest X-ray accounts for a significant proportion of radiological examinations. It is valuable to explore more methods for improving performance.
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http://dx.doi.org/10.1186/s12880-021-00627-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194196PMC
June 2021

[Preclinical developments of treatment options for retinal dystrophy in neuronal ceroid lipofuscinosis].

Ophthalmologe 2021 07 4;118(7):769-770. Epub 2021 Jun 4.

Klinik und Poliklinik für Augenheilkunde, Experimentelle Ophthalmologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.

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http://dx.doi.org/10.1007/s00347-021-01419-zDOI Listing
July 2021

Moderately Hypofractionated Once-Daily Compared With Twice-Daily Thoracic Radiation Therapy Concurrently With Etoposide and Cisplatin in Limited-Stage Small Cell Lung Cancer: A Multicenter, Phase II, Randomized Trial.

Int J Radiat Oncol Biol Phys 2021 10 13;111(2):424-435. Epub 2021 May 13.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Lung Cancer Institute of Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China. Electronic address:

Purpose: Chemotherapy and concurrent thoracic radiation therapy (CCTRT) followed by prophylactic cranial irradiation (PCI) is the standard of care for limited-stage small cell lung cancer (LS-SCLC). We aimed to compare the efficacy and toxicity of moderately hypofractionated once-daily CCTRT with that of a standard twice-daily regimen.

Methods And Materials: This multicenter, phase 2, randomized study enrolled patients aged 18 to 75 years old who had pathologically confirmed LS-SCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received 4 to 6 cycles of etoposide-cisplatin chemotherapy and were randomized to receive twice-daily CCTRT at 45 Gray (Gy) in 30 fractions or once-daily CCTRT at 65 Gy in 26 fractions, commencing with cycles 1 to 3 of chemotherapy. PCI was given to good responders. The primary endpoint was progression-free survival (PFS).

Results: The analyses included 182 patients, with 94 in the twice-daily group and 88 in the once-daily group. CCTRT started with cycle 3 of chemotherapy for most patients (80.2%). At a median follow-up of 24.3 months, the median PFS was 13.4 months (95% confidence interval [CI], 10.8-16.0) in the twice-daily group versus 17.2 months (95% CI, 11.8-22.6) in the once-daily group (P = .031), with 2-year PFS rates of 28.4% (95% CI, 18.2-38.6) and 42.3% (95% CI, 31.1-53.5), respectively. The estimated overall survival was 33.6 months in the twice-daily group versus 39.3 months in the once-daily group (P = .137). The median locoregional PFS was 23.9 months in the twice-daily group and was not reached in the once-daily group (P = .017). The incidences of most toxicities were similar in both groups, except for a higher incidence of ≥grade 3 acute lymphopenia in the once-daily group (71.7% vs 40.2% in the twice-daily group; P < .001). There was no difference in the incidences of ≥grade 3 esophagitis (17.4% vs 15.3%, respectively), pneumonitis (3.3% vs 2.4%, respectively) or treatment-related death (2.2% vs 1.2%, respectively) between the once-daily and twice-daily groups.

Conclusions: Moderately hypofractionated, once-daily CCTRT showed improved PFS and similar toxicities compared with twice-daily CCTRT in LS-SCLC. This regimen should be evaluated for comparison in a phase 3 randomized trial.
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http://dx.doi.org/10.1016/j.ijrobp.2021.05.003DOI Listing
October 2021

[Corrigendum] GINS2 is a novel prognostic biomarker and promotes tumor progression in early‑stage cervical cancer.

Oncol Rep 2021 May 22;45(5). Epub 2021 Apr 22.

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, P.R. China.

Subsequently to the publication of the above article, the authors have realized that Figs. 2 and 6 each contained an incorrectly assembled data panel: Essentially, a couple of the data panels had been inadvertently selected twice for these figures. The corrected versions of Figs 2 and 6, including the correct data for the H&E staining of the tissue of patient 4 in Fig. 2C and the invaded cells of RNAi#2 of the Siha cell line in Fig. 6C, are shown below and on the next page. All the authors agree to the publication of this Corrigendum, and they thank the Editor of for allowing them the opportunity to publish it. Furthermore, they apologize to the readership for any inconvenience caused. [The original article was published in  37: 2652‑2662, 2017; DOI: 10.3892/or.2017.5573].
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http://dx.doi.org/10.3892/or.2021.8016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020209PMC
May 2021

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice-An Animal Model of CLN10 Disease.

Cells 2021 03 21;10(3). Epub 2021 Mar 21.

Department of Ophthalmology, Experimental Ophthalmology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Vision loss is among the characteristic symptoms of neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative lysosomal storage disorder. Here, we performed an in-depth analysis of retinal degeneration at the molecular and cellular levels in mice lacking the lysosomal aspartyl protease cathepsin D, an animal model of congenital CLN10 disease. We observed an early-onset accumulation of storage material as indicated by elevated levels of saposin D and subunit C of the mitochondrial ATP synthase. The accumulation of storage material was accompanied by reactive astrogliosis and microgliosis, elevated expression of the autophagy marker sequestosome 1/p62 and a dysregulated expression of several lysosomal proteins. The number of cone photoreceptor cells was reduced as early as at postnatal day 5. At the end stage of the disease, the outer nuclear layer was almost atrophied, and all cones were lost. A significant loss of rod and cone bipolar cells, amacrine cells and ganglion cells was found at advanced stages of the disease. Results demonstrate that cathepsin D deficiency results in an early-onset and rapidly progressing retinal dystrophy that involves all retinal cell types. Data of the present study will serve as a reference for studies aimed at developing treatments for retinal degeneration in CLN10 disease.
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http://dx.doi.org/10.3390/cells10030696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003850PMC
March 2021

Lycopene inhibits IL-1β-induced inflammation in mouse chondrocytes and mediates murine osteoarthritis.

J Cell Mol Med 2021 04 10;25(7):3573-3584. Epub 2021 Mar 10.

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

Osteoarthritis (OA) is a common chronic degenerative condition in the elderly, in which inflammation plays a key role in disease pathology. Lycopene (Lye), a member of the carotenoid family, has been reported to have anti-inflammatory effects. The purpose of this study was to investigate the effect of Lye on the inflammation of chondrocytes and the mouse OA model. Chondrocytes were treated with interleukin (IL)-1β, and the mouse OA model was induced by the surgical destabilization of the medial meniscus (DMM). The results showed that Lye could inhibit the expression of inflammatory factors and alleviate the degradation of extracellular matrix (ECM). Additionally, Lye could activate the Nrf2/HO-1 pathway and reverse the activations of NF-κB and STAT3 signal pathway induced by IL-1β, suggesting that its anti-inflammatory effect may be mediated via these pathways. The animal experiments showed that Lye could decrease the Osteoarthritis Research Society International (OARSI) scores of the knee, indicating that it could inhibit the occurrence and development of OA in mouse. Overall, our results indicated that Lye might be used as a novel drug for OA treatment.
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http://dx.doi.org/10.1111/jcmm.16443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034440PMC
April 2021

SIRT3-mediated deacetylation of NLRC4 promotes inflammasome activation.

Theranostics 2021 15;11(8):3981-3995. Epub 2021 Feb 15.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.

() infection of macrophage induces NLRC4 inflammasome-mediated production of the pro-inflammatory cytokines IL-1β. Post-translational modifications on NLRC4 are critical for its activation. Sirtuin3 (SIRT3) is the most thoroughly studied mitochondrial nicotinamide adenine dinucleotide (NAD) -dependent deacetylase. We wondered whether SIRT3 mediated-deacetylation could take part in NLRC4 inflammasome activation. We initially tested IL-1β production and pyroptosis after cytosolic transfection of flagellin or infection in wild type and SIRT3-deficient primary peritoneal macrophages via immunoblotting and ELISA assay. These results were confirmed in SIRT3-deficient immortalized bone marrow derived macrophages (iBMDMs) which were generated by CRISPR-Cas9 technology. In addition, experiments were conducted to confirm the role of SIRT3 in -induced cytokines production. Then NLRC4 assembly was analyzed by immune-fluorescence assay and ASC oligomerization assay. Immunoblotting, ELISA and flow cytometry were performed to clarify the role of SIRT3 in NLRP3 and AIM2 inflammasomes activation. To further investigate the mechanism of SIRT3 in NLRC4 activation, co-immunoprecipitation (Co-IP), we did immunoblot, cellular fractionation and in-vitro deacetylation assay. Finally, to clarify the acetylation sites of NLRC4, we performed liquid chromatography-mass spectrometry (LC-MS) and immunoblotting analysis. SIRT3 deficiency led to significantly impaired NLRC4 inflammasome activation and pyroptosis both and . Furthermore, SIRT3 promotes NLRC4 inflammasome assembly by inducing more ASC speck formation and ASC oligomerization. However, SIRT3 is dispensable for NLRP3 and AIM2 inflammasome activation. Moreover, SIRT3 interacts with and deacetylates NLRC4 to promote its activation. Finally, we proved that deacetylation of NLRC4 at Lys71 or Lys272 could promote its activation. Our study reveals that SIRT3 mediated-deacetylation of NLRC4 is pivotal for NLRC4 activation and the acetylation switch of NLRC4 may aid the clearance of infection.
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http://dx.doi.org/10.7150/thno.55573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914345PMC
July 2021

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Circulation 2021 May 5;143(20):2007-2022. Epub 2021 Mar 5.

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).

Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

Methods: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

Results: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050812DOI Listing
May 2021

Butylphthalide Inhibits Autophagy and Promotes Multiterritory Perforator Flap Survival.

Front Pharmacol 2020 29;11:612932. Epub 2021 Jan 29.

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

Multiterritory perforator flap is an important plastic surgery technique, yet its efficacy can be limited by partial necrosis at the choke Ⅱ zone. Butylphthalide (NBP) has been used for many diseases but has not been studied in the multiterritory perforator flap. With the effect of NBP, we observed increasing in capillary density, inhibition of autophagy and oxidative stress, and a reduction in apoptosis of cells, all consistent with increased flap survival. However, the protective effect of NBP on multiterritory perforator flap was lost following administration of the autophagy agonist rapamycin (Rap). Through the above results, we assumed that NBP promotes flap survival by inhibiting autophagy. Thus, this study has found a new pharmacological effect of NBP on the multiterritory perforator by inhibiting autophagy to prevent distal postoperative necrosis and exert effects on angiogenesis, oxidative stress, and apoptosis within the flap.
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http://dx.doi.org/10.3389/fphar.2020.612932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878674PMC
January 2021

Gastrodin Promotes the Survival of Random-Pattern Skin Flaps via Autophagy Flux Stimulation.

Oxid Med Cell Longev 2021 9;2021:6611668. Epub 2021 Jan 9.

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

The random-pattern flap has a significant application in full mouth restoration (reconstructive surgery) and plastic surgery owing to an easy operation with no axial vascular restriction. However, distal necrosis after flap operation is still considered the most common complication which makes it the Achilles heel in the clinical application of random-pattern flaps. A Chinese medicinal herb named gastrodin is an effective active ingredient of . Herein, the existing study explored the significant potential of gastrodin on flap survival and its underlying mechanism. Our obtained results show that gastrodin will significantly improve flap survival, reduce tissue edema, and increase blood flow. Furthermore, our studies reveal that gastrodin can promote angiogenesis and reduce the apoptotic process as well as oxidative stress. The results of immunohistochemistry and immunoblotting revealed that gastrodin has a role in the elevation of autophagy flux which results in induced autophagy. The use of 3MA (3-methyladenine) for the inhibition of induced autophagy significantly weakened the underlying benefits of gastrodin treatment. Taken together, our obtained results confirmed that gastrodin is an effective drug that can considerably promote the survival rate of flaps (random pattern) via enhancing autophagy. Enhanced autophagy is correlated with the elevation of angiogenesis, reduced level of oxidative stress, and inhibition of cell apoptosis.
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http://dx.doi.org/10.1155/2021/6611668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811417PMC
September 2021

The landscape of kinase domain duplication in Chinese lung cancer patients.

Ann Transl Med 2020 Dec;8(24):1642

Department of Medical Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Kinase domain duplication (KDD) is a special type of large genomic rearrangement (LGR), occurring in the kinase domain of protein kinase genes. KDD of some lung cancer driver genes, such as.

Egfr: KDD, has been identified and implicated to be oncogenic in non-small cell lung cancer (NSCLC). The present study aims to interrogate the spectrum of KDD occurring on classic driver genes in Chinese lung cancer patients without the presence of classic lung cancer driver mutations.

Methods: We retrospectively enrolled 10,525 Chinese lung cancer patients who met the following inclusion criteria; (I) do not carry classic lung cancer driver mutations in any of the 8 driver genes and (II) tyrosine kinase inhibitor (TKI)-naïve. Capture-based targeted sequencing was performed on tissue or plasma samples. LGR and KDD were identified by using in-house analysis scripts. The prevalence and distribution of LGR and KDD in our cohort were analyzed.

Results: The median age of the cohort was 64 years with 68.7% being male. Among all patients, 23.2% and 51.8% were diagnosed with stage III and IV disease respectively. We identified 43 cases (0.41%) harboring LGR in one of the driver genes (), with 24 (0.23%) patients harboring KDD. Of the patients harboring KDD, a majority (n=19) harbored canonical -KDD involving exons 18-25, whilst one patient harbored duplications of exons 18-26. There were three -KDD patients; in two, the alteration occurred in exons 15-21 and in one, the alteration occurred in exons 3-21. One patient harbored -KDD involving exons 12-18. KDD showed a comparable prevalence in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (0.33% 0.11%, P=0.118). Nineteen non-KDD LGRs, spanning six genes including (n=6), (n=3), (n=4), (n=2), (n=2) and (n=2), were found, each occurring in one patient. The prevalence of LGR in LUADs and LUSCs was comparable (0.55% 0.38%, P=0.452).

Conclusions: We observed a prevalence of 0.41% and 0.23% for LGR and KDD, respectively. Twenty-four different LGR alterations, including 5 KDDs and 19 non-KDD LGRs, were observed. KDDs mainly occurred in involving exons 18-25 and non-KDD LGRs were distributed more randomly. The prevalence of LGR/KDD in LUSCs and LUADs was comparable.
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http://dx.doi.org/10.21037/atm-20-7408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812209PMC
December 2020

Response by Xu et al to Letter Regarding Article, "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets".

Circulation 2020 12 14;142(24):e452-e453. Epub 2020 Dec 14.

Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China (Y.X., H.J., J.L.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051367DOI Listing
December 2020

Highly Conductive Nitrogen-Doped Vertically Oriented Graphene toward Versatile Electrode-Related Applications.

ACS Nano 2020 Nov 12;14(11):15327-15335. Epub 2020 Nov 12.

Center for Nanochemistry (CNC), College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People's Republic of China.

The direct growth of vertically oriented graphene (VG) on low-priced, easily accessible soda-lime glass can propel its applications in transparent electrodes and energy-relevant areas. However, graphene deposited at low temperature (∼600 °C) on the catalysis-free insulating substrates usually presents high defect density, poor crystalline quality, and unsatisfactory electrical conductivity. To tackle this issue, we select high borosilicate glass as the growth substrate (softening point ∼850 °C), which can resist higher growth temperature and thus afford higher graphene crystalline quality, by using a radio-frequency plasma-enhanced chemical vapor deposition (rf-PECVD) route. A nitrogen doping strategy is also combined to tailor the carrier concentration through a methane/acetonitrile-precursor-based synthetic strategy. The sheet resistance of as-grown nitrogen-doped (N-doped) VG films on high borosilicate glass can thus be lowered down to ∼2.3 kΩ·sq at a transmittance of 88%, less than half of the methane-precursor-based PECVD product. Significantly, this synthetic route allows the achievement of 30-inch-scale uniform N-doped graphene glass, thus promoting its applications as excellent electrodes in high-performance switchable windows. Additionally, such N-doped VG films were also employed as efficient electrocatalysts for electrocatalytic hydrogen evolution reaction.
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http://dx.doi.org/10.1021/acsnano.0c05662DOI Listing
November 2020

[Experimental therapeutic approaches for the treatment of retinal dystrophy in neuronal ceroid lipofuscinosis].

Ophthalmologe 2021 Feb;118(2):106-112

Klinik und Poliklinik für Augenheilkunde, Experimentelle Ophthalmologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.

Background: Neuronal ceroid lipofuscinosis (NCL) is a group of rare and fatal neurodegenerative lysosomal storage diseases. Progressive retinal degeneration and loss of vision are among the characteristic symptoms of affected patients. A brain-directed enzyme replacement therapy has been shown to significantly attenuate the neurological symptoms in CLN2 patients and is currently the only approved therapy for NCL; however, there is presently no treatment option for retinal dystrophy in NCL.

Objective: This short review aims to give an overview of preclinical studies that have developed and evaluated therapeutic strategies for the treatment of retinal dystrophy in animal models of different NCL forms.

Material And Methods: The key findings of preclinical studies that have achieved positive therapeutic effects on retinal structure and/or function using different treatment strategies are summarized and discussed.

Results And Conclusion: The published data on preclinical studies demonstrate the efficacy of different therapeutic strategies to attenuate retinal degeneration and vision loss in animal models for different NCL forms. It remains to be seen whether these promising results can be confirmed in future clinical studies.
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http://dx.doi.org/10.1007/s00347-020-01237-9DOI Listing
February 2021

Corrigendum to "Knockout of P2Y12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells" [Brain Behav. Immun. 62 (2017) 245-255].

Brain Behav Immun 2021 Jan 26;91:801-803. Epub 2020 Sep 26.

Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2020.09.020DOI Listing
January 2021

PAK Membrane Translocation and Phosphorylation Regulate Platelet Aggregation Downstream of Gi and G12/13 Pathways.

Thromb Haemost 2020 Nov 27;120(11):1536-1547. Epub 2020 Aug 27.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Platelet activation plays a pivotal role in physiological hemostasis and pathological thrombosis causing heart attack and stroke. Previous studies conclude that simultaneous activation of Gi and G signaling pathways is sufficient to cause platelet aggregation. However, using Gq knockout mice and Gq-specific inhibitors, we here demonstrated that platelet aggregation downstream of coactivation of Gi and G depends on agonist concentrations; coactivation of Gi and G pathways only induces platelet aggregation under higher agonist concentrations. We confirmed Gi and G pathway activation by showing cAMP (cyclic adenosine monophosphate) decrease and RhoA activation in platelets stimulated at both low and high agonist concentrations. Interestingly, we found that though Akt and PAK (p21-activated kinase) translocate to the platelet membrane upon both low and high agonist stimulation, membrane-translocated Akt and PAK only phosphorylate at high agonist concentrations, correlating well with platelet aggregation downstream of concomitant Gi and G pathway activation. PAK inhibitor abolishes Akt phosphorylation, inhibits platelet aggregation in vitro and arterial thrombus formation in vivo. We propose that the PAK-PI3K/Akt pathway mediates platelet aggregation downstream of Gi and G and PAK may represent a potential antiplatelet and antithrombotic target.
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http://dx.doi.org/10.1055/s-0040-1714745DOI Listing
November 2020

Old yellow enzymes: structures and structure-guided engineering for stereocomplementary bioreduction.

Appl Microbiol Biotechnol 2020 Oct 24;104(19):8155-8170. Epub 2020 Aug 24.

Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe, Shenyang, 110016, People's Republic of China.

Since the first discovery of old yellow enzyme 1 (OYE1) from Saccharomyces pastorianus in 1932, biocatalytic asymmetric reduction of activated alkenes by OYEs has become a valuable reaction in organic synthesis. To access stereocomplementary C=C-bond bioreduction, the mining of novel OYEs and especially the protein engineering of existing OYEs have been performed, which successfully achieved the stereocomplementary reduction in several cases and further raise the potential of applications. In this review, we analyzed the structures, active sites, and substrate recognition of OYEs, which are the bases for their substrate specificity and stereospecificity. Sequence similarity network of OYEs superfamily was also constructed to investigate the scope of characterized OYEs. The structure-guided engineering to switch the stereoselectivity of OYEs and thus access stereocomplementary bioreduction over the last decade (2009-2020) was then reviewed and discussed, which might give new insights into the mining and engineering of related biocatalysts. KEY POINTS: • The sequence similarity network of OYEs superfamily was constructed and annotated. • The structures and active sites of OYEs from different classes were compared. • "Left/right" binding mode was used to explain the stereopreferences of OYEs. • Structure-guided engineering of OYEs to switch their stereoselectivity was reviewed.
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http://dx.doi.org/10.1007/s00253-020-10845-zDOI Listing
October 2020

Associations between the serum levels of PFOS/PFOA and IgG N-glycosylation in adult or children.

Environ Pollut 2020 Oct 18;265(Pt A):114285. Epub 2020 Mar 18.

Wuhan Centers for Disease Prevention and Control, Wuhan, 430015, China. Electronic address:

Background: Perfluorooctanoic acid (PFOA) and perfluorooctanoic sulfonate (PFOS) have been shown to be associated with disease development. Immunoglobulin G (IgG) N-glycosylation plays a vital role in human immune system and inflammatory activities. Altered IgG glycosylation was one of the molecular markers of various disorders. However, whether the chemicals affect IgG glycosylation has not been investigated.

Methods: Serum samples of 190 individuals including 95 adults and 95 children were selected based on the sex, age and PFOA/PFOS concentration. IgG N-glycome profile was obtained from glycan release, derivatization, and MALDI-MS analysis. One-factor ANOVA test was performed to analyze the association between different levels of PFOS/PFOA and IgG glycosylation changes. Evaluation of the diagnostic performance of significantly changed IgG glycosylation was performed by receiver operating characteristic curve. PFOS/PFOA concentrations were studied in relation to IgG glycosylation by 3D-nonlinear regression analysis.

Results: 10 of the 28 individual IgG glycans were significantly altered between different levels of PFOS/PFOA in adult serum. Among children with high serum levels of PFOS or PFOA, a total of 12 IgG N-glycans were markedly different from those with lower serum PFOS/PFOA. The glycan derived traits for adults with higher serum PFOS or PFOA were marked by significant alterations in IgG digalactosylation, agalactosylation, fucosylation, fucosylated sialylation, and disialylation. Similarly, pronounced changes in agalactosylation, digalactosylation, mono-sialylation and total sialylation, as well as neutral and sialo bisection, were associated with elevated serum PFOS or PFOA in children. Several glycans gained moderately accurate scores of area under the curve for diagnosis of PFOS or PFOA pollution. Nonlinear surface fitting showed the independent or coordinate effect of PFOS or PFOA on the expression of IgG glycosylation.

Conclusions: High levels of PFOS or PFOA in human serum were strongly associated with altered IgG glycosylation and therefore are a potential risk factor for the development of diseases.
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http://dx.doi.org/10.1016/j.envpol.2020.114285DOI Listing
October 2020

Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice.

Metabolism 2020 10 23;111:154324. Epub 2020 Jul 23.

Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China. Electronic address:

Background: Clinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells.

Methods: Two diabetic mouse models, db/db mice and pancreatic alpha cell lineage-tracing (glucagon-β-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25-25 μmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined.

Results: Treatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels in db/db mice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU double-positive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even co-localized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (including Pdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression of Pcsk1 (which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation of Pdx1 expression was attenuated by GLP-1 receptor antagonist.

Conclusions: Except for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediated via GLP-1 secreted from alpha cells.
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http://dx.doi.org/10.1016/j.metabol.2020.154324DOI Listing
October 2020

Superclean Growth of Graphene Using a Cold-Wall Chemical Vapor Deposition Approach.

Angew Chem Int Ed Engl 2020 Sep 29;59(39):17214-17218. Epub 2020 Jul 29.

Center for Nanochemistry, Beijing Science and Engineering Center for Nanocarbons, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, P. R. China.

Chemical vapor deposition (CVD) has become a promising approach for the industrial production of graphene films with appealing controllability and uniformity. However, in the conventional hot-wall CVD system, CVD-derived graphene films suffer from surface contamination originating from the gas-phase reaction during the high-temperature growth. Shown here is that the cold-wall CVD system is capable of suppressing the gas-phase reaction, and achieves the superclean growth of graphene films in a controllable manner. The as-received superclean graphene film, exhibiting improved optical and electrical properties, was proven to be an ideal candidate material used as transparent electrodes and substrate for epitaxial growth. This study provides a new promising choice for industrial production of high-quality graphene films, and the finding about the engineering of the gas-phase reaction, which is usually overlooked, will be instructive for future research on CVD growth of graphene.
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http://dx.doi.org/10.1002/anie.202005406DOI Listing
September 2020

Protective effect of puerarin against burn-induced heart injury in rats.

Exp Ther Med 2020 Jul 29;20(1):275-282. Epub 2020 Apr 29.

Department of Burn, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.

The present study evaluated the potential protective effects of puerarin and its associated mechanism on burn-induced myocardial damage. A total of 40 healthy adult Wistar rats were randomly divided into four groups: i) Sham; ii) burn; iii) burn + puerarin; and iv) puerarin. Serum levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6 were measured using ELISA. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were determined in myocardial homogenates using a commercial assay kit. TUNEL staining and western blot analysis of cleaved and pro-caspase-3 were also performed to assess apoptosis. Activation of p38-MAPK, ERK, JNK and AKT were measured using western blot analysis. Left ventricular systolic pressure, maximum rates of increase/decrease in left ventricular pressure, creatine kinase MB activity and cardiac troponin T levels were found to be altered in the burn group 12 h after burn, which were reversed by puerarin treatment. Injection of puerarin following burn injury also reduced heart water content. Serum levels of IL-1β, TNF-α and IL-6 were significantly higher in the burn group compared with those in the sham group. Puerarin treatment reduced serum levels of IL-1β, TNF-α and IL-6, in addition to reducing MPO activity and MDA levels in myocardial tissues. Puerarin inhibited the activation of caspase-3, p38, ERK and JNK following severe burn, but elevated Akt activation following severe burn. In conclusion, puerarin improved cardiac function in rats following severe burn injury, which may be due to reduced myocardial injury, inhibition of cardiomyocyte apoptosis and reduced oxidative inflammatory stress; the MAPK and AKT signaling pathways are proposed to the underlying mechanism of these findings.
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http://dx.doi.org/10.3892/etm.2020.8696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282049PMC
July 2020
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