Publications by authors named "Liangliang Jia"

24 Publications

  • Page 1 of 1

Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3.

Arterioscler Thromb Vasc Biol 2021 05 25;41(5):1710-1723. Epub 2021 Mar 25.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.315805DOI Listing
May 2021

Cutting environmental footprints of maize systems in China through Nutrient Expert management.

J Environ Manage 2021 Mar 11;282:111956. Epub 2021 Jan 11.

Ministry of Agriculture Key Laboratory of Plant Nutrition and Fertilizer, Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100081, PR China. Electronic address:

Excessive fertilizer consumption, poor management, and intense pollution currently restrict sustainable agriculture in China. To address these problems, two 9-year experiments involving typical maize production systems in Northcentral China (summer maize) and Northeast China (spring maize) were conducted to evaluate the effectiveness of Nutrient Expert (NE) management, a Nutrient Decision Support System which combines 4 R nutrient management with improved varieties and optimized plant density, on reducing carbon (C) and nitrogen (N) footprints. The mean grain yields under NE were 7.4 and 11.5 tons ha, which were 3.9% and 6.9% higher than those of local farmers' practices (FP) in the summer and spring maize systems, respectively; the N-derived (affected by N fertilization) yield accounted for 21.7% and 73.5% of the total yield under NE, respectively. Compared with FP, NE achieved 21.8% and 16.0% lower reactive nitrogen (Nr) losses, 18.4% and 20.9% lower greenhouse gas (GHG) emissions, 24.8% and 21.4% smaller N footprints (9.1 and 2.3 kg N ton grain), and 21.5% and 26.0% smaller C footprints (436 and 206 kg CO eq ton grain) in summer and spring maize, respectively. NE reduced the N-derived N and C footprints by 30.3% and 27.2% in summer maize and 22.9% and 28.0% in spring maize, respectively, as a result of greater yields and optimal N management. Moreover, compared with summer maize, spring maize showed significantly smaller N-derived N (12.6-fold) and C (7.2-fold) footprints. The results demonstrated the ability of long-term NE management to sustain maize yields, reduce Nr losses and GHG emissions, and cut C and N footprints, indicating its potential suitability as an alternative management for sustainable agriculture. Moreover, the summer maize system still had considerable potential for environmental footprints reduction even when current NE management practices were adopted.
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http://dx.doi.org/10.1016/j.jenvman.2021.111956DOI Listing
March 2021

Estimation of nitrogen supply for winter wheat production through a long-term field trial in China.

J Environ Manage 2020 Sep 20;270:110929. Epub 2020 Jun 20.

Hebei Fertilizer Technology Innovation Center, Institute of Agricultural Resources and Environment, Hebei Academy of Agriculture and Forestry Sciences, Shijiazhuang, 050051, PR China. Electronic address:

Excessive synthetic nitrogen (N) applications, high mineral N accumulation and low N use efficiency (NUE) are current issues in intensively cultivated winter wheat production system impeding the sustainable development of agriculture in China. To solve these problems, soil accumulated N in the top 1 m of the soil profile before sowing (N), returned straw-N from the previous maize crop (N) and fertilizer N application (N) should be comprehensively considered N supply sources in N management. As such, the objective of this research was to determine the optimal total N supply (TN) level needed to meet crop requirements while minimizing environmental impacts. A 9-year on-farm experiment was conducted in accordance with a split-plot design involving two different fertilizer management systems (main treatments) and three N application strategies (sub treatments). Extensive TN levels (ranging from 61 kg ha to 813 kg ha) were detected, and relative yield (RY), N input and N output in response to the TN were measured. The relationships between TN and RY, N input, and N output strongly fit linear-plateau, linear, and linear-plateau models, respectively. The minimum TN levels needed to achieve the maximum RY and N output were 325 and 392 kg ha, respectively. On the basis of N supply capacity, the TN was removed from the growing system by 61% (N input). As the N input increased past 209 kg ha, the NUE declined, at which point the TN reached 433 kg ha. Therefore, the suitable TN should range from 325 kg ha (ensuring a total N supply for high yield and N uptake) to 433 kg ha (obtaining a relatively higher NUE and less N loss to the environment). The TN was highlighted to be an indicator for use in N management recommendations. Considering the average high N accumulation in winter wheat production systems, N management should essentially take into account the consumption of N, the levels of N and the minimum application of N to obtain high yields while minimizing environmental impacts under suitable TN levels.
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http://dx.doi.org/10.1016/j.jenvman.2020.110929DOI Listing
September 2020

Formaldehyde and VOC emissions from plywood panels bonded with bio-oil phenolic resins.

Environ Pollut 2020 Sep 16;264:114819. Epub 2020 May 16.

Key Comprehensive Laboratory of Forestry, Shaanxi Province, China; College of Forestry, Northwest A&F University, Yangling, 712100, Shaanxi, China. Electronic address:

Pyrolysis bio-oil was used to partially substitute for phenol in reacting with formaldehyde for the production of bio-oil phenol formaldehyde plywood (BPFP) panels, with the phenol substitution ratio being 20%, 40%, or 60%. Emissions of formaldehyde and volatile organic compounds (VOCs) from the BPFP panels were studied using solid-phase micro-extraction (SPME) followed by headspace gas chromatography/mass spectrometry (GC/MS), and were compared to those from the phenol formaldehyde plywood (PFP) panels. The sources for VOCs were analyzed, and the health risks associated with the BPFP were examined. Results showed that at 80 °C: (1) Formaldehyde emissions from the BPFP panels were increased to about 4 times that of PFP; (2) VOCs emissions were significantly reduced by up to 84.9% mainly due to the greatly reduced phenol emissions, although the total number of VOCs was increased from 20 to 35; (3) BPFP presents greatly increased carcinogenic and non-carcinogenic health risks because of its much stronger emissions of formaldehyde, N,N-dimethylformamide, benzofuran, furfural, and many chemicals from the bio-oil. It is highly advisable that the health risks are properly taken care of before the wide application of BPFP, or similar bio-oil based engineered wood products.
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http://dx.doi.org/10.1016/j.envpol.2020.114819DOI Listing
September 2020

Data on Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation in vitro.

Data Brief 2020 Feb 19;28:105023. Epub 2019 Dec 19.

Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.

The Tougu Xiaotong capsule (TXC) is a traditional herbal compound used to treat osteoarthritis (OA) in China. We performed fingerprint analysis with HPLC for the quality control of TXC. Its composition was identified by the comparison of the spectrogram and chromatographic peak of retention time with a reference substance. TXC was found to contain paeoniflorin, isofraxidin, ferulic acid, and rosmarinic acid. The chondrocytes were identified by immunohistochemical staining using collagen II. Chondrocytes that were positive for collagen II were stained brown in the cytoplasm. The toll-like receptor 4 (TLR4) was expressed on the chondrocyte membrane, which was observed using immunofluorescence microscopy. The nuclei were stained blue by 4',6-diamidino-2-phenylindole (DAPI) and TLR4 was stained green. These were observed using laser scanning confocal microscopy. The successful establishment of LPS-exposed chondrocytes was confirmed using enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) administration significantly reduced the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and a maximum effect was observed at 8 h. We believe that these methods will be useful in future investigations of OA. This data article is related to the research article "Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation: and verification" [1].
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http://dx.doi.org/10.1016/j.dib.2019.105023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939087PMC
February 2020

Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation: In vivo and in vitro verification.

J Ethnopharmacol 2020 Mar 21;249:112390. Epub 2019 Nov 21.

Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China; Department of Neurosurgery, Hamamatsu University School of Medicine, Handayama, 1-20-1, Higashi-ku, Hamamatsu-city, Shizuoka, 431-3192, Japan. Electronic address:

Ethnopharmacological Relevance: Tougu Xiaotong capsules (TXC) are an herbal compound commonly used to treat osteoarthritis (OA) in China.

Aim Of The Study: We attempted to verify TXC's therapeutic effects and mechanisms related to the p38 mitogen-activated protein kinase (MAPK) pathway in vivo and in vitro.

Materials And Methods: TXC's therapeutic effects were assessed by observing cartilage degeneration and inflammatory factors in a modified Hulth's model (in vivo) and a lipopolysaccharides (LPS)-exposed cellular model (in vitro). The expression of biomarkers related to p38 MAPK pathway-mediated inflammation was also investigated.

Results: TXC treatment reversed cartilage degeneration related biomarkers (ADAMTS 4, ADAMTS 5, Col I, Col V, MMP 3, MMP 9, and MMP 13) and inflammation factors (IL-1β, TNF-α, and IL-6) in both the animal and cellular OA models. Expression of p-p38 MAPK was downregulated following TXC administration, and changes to microRNAs in the cellular models were recovered. These results indicated that the p38 MAPK pathway-related mechanism may involve therapeutic effects of TXC.

Conclusions: This study verified TXC's efficacy to treat OA in vivo and in vitro and suggests that p38 MAPK pathway-related mechanisms may be involved in TXC's therapeutic effects.
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http://dx.doi.org/10.1016/j.jep.2019.112390DOI Listing
March 2020

The responses of extracellular enzyme activities and microbial community composition under nitrogen addition in an upland soil.

PLoS One 2019 30;14(9):e0223026. Epub 2019 Sep 30.

Ministry of Agriculture Key Laboratory of Plant Nutrition and Fertilizer, Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences (CAAS), Beijing, PR China.

Tremendous amounts of nitrogen (N) fertilizer have been added to arable lands, often resulting in substantial effects on terrestrial ecosystems, including soil acidification, altered enzyme activities and changes in microbial community composition. Soil microbes are the major drivers of soil carbon (C) and N cycling; therefore, understanding the response of microbial communities to elevated N inputs is of significant importance. This study was carried out to investigate the influences of different N fertilization rates (0, 182, and 225 kg ha-1 representing control, low, and high N supply for each crop season for summer maize and winter wheat) on soil biochemical attributes, extracellular enzyme activities, and the microbial community composition in a winter wheat-summer maize rotation cropping system in north-central China. The results showed that N addition significantly decreased the soil pH in both the wheat and maize seasons. Microbial biomass N (MBN) decreased following N fertilization in the wheat season, while the opposite trend in MBN was observed in the maize season. Response ratio analysis showed that the activities of enzymes involved in C, N, and phosphorus cycling were significantly enhanced under N enrichment in both the wheat and maize seasons, and higher enzyme activities were noted in the high N addition treatment than in the low N addition treatment. A linear increase in fungal abundance with the N addition gradient was observed in the wheat season, whereas the fungal abundance increased and then decreased in the maize season. The bacterial abundance showed an increased and then decreased trend in response to the N addition gradient in both the wheat and maize crop seasons. Moreover, the partial least squares path model (PLS-PM) analysis showed that soil pH and soil organic carbon (SOC) were the most important soil variables, causing shifts in the soil bacteria. Furthermore, compared with the N-cycling enzymes, the C-cycling enzymes were significantly affected by the soil pH and SOC. Taken together, these results suggest that the effect of N addition on enzyme activities was consistent in both crop seasons, while the effects on MBN and microbial community composition to N addition were highly variable in the two crop seasons. Moreover, N fertilization-induced changes in the soil chemical properties such as soil acidity and SOC played a substantial role in shaping the microbial community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768454PMC
March 2020

Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development.

Atherosclerosis 2019 10 25;289:64-72. Epub 2019 Aug 25.

Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China. Electronic address:

Background And Aims: Abdominal aortic aneurysm (AAA) is characterized by infiltration of inflammatory cells, extracellular matrix (ECM) degradation, and dysfunction of vascular smooth muscle cells (VSMCs). Recent studies reported that exosomes mediate intercellular communication and are involved in different diseases. Whether exosomes play a role in AAA is poorly understood. Hence, this study evaluated the function of exosomes in AAA development.

Methods: The presence of exosomes in human and calcium phosphate (CaPO)-induced AAA tissues was determined by immunofluorescence staining of CD63 and Alix. GW4869, an inhibitor of exosome biogenesis, was intraperitoneally injected into CaPO-induced AAA tissues to evaluate the effects of exosomal inhibition on AAA development. To explore the underlying mechanisms, the human monocytic cell line THP-1 was differentiated into macrophages, and exosomes were collected from macrophages. VSMCs were treated with macrophage-derived exosomes, and the expression of matrix metalloproteinase-2 (MMP-2) was evaluated. The activation of mitogen-activated protein kinases (MAPKs) pathways was also investigated in vitro and in vivo.

Results: Exosomes were detected in the adventitia of aneurysmal tissues obtained from humans and mice. They were mainly expressed in clusters of macrophages. Intraperitoneal injection of GW4869 for two weeks significantly attenuated the progression of CaPO-induced AAA, preserved elastin integrity and decreased MMP-2 expression. Similarly, administration of GW4869 suppressed the systemic and aneurysmal exosome generation. In vitro, treatment with macrophage-derived exosomes elevated MMP-2 expression in human VSMCs, while pre-treatment with GW4869 abolished these effects. It was also found that JNK and p38 pathways mediated the production of MMP-2 in VSMCs following treatment with macrophage-derived exosomes.

Conclusions: This study suggests that exosomes derived from macrophages are involved in the pathogenesis of AAA. Macrophage-derived exosomes trigger MMP-2 expression in VSMC via JNK and p38 pathways. GW4869 supplementation attenuates CaPO-induced AAA in mice.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.016DOI Listing
October 2019

Rabies Virus Pseudotyped with CVS-N2C Glycoprotein as a Powerful Tool for Retrograde Neuronal Network Tracing.

Neurosci Bull 2020 Mar 23;36(3):202-216. Epub 2019 Aug 23.

Shenzhen Key Lab of Neuropsychiatric Modulation and Collaborative Innovation Center for Brain Science, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Center for Excellence in Brain Science and Intelligence Technology, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China.

Efficient viral vectors for mapping and manipulating long-projection neuronal circuits are crucial in structural and functional studies of the brain. The SAD strain rabies virus with the glycoprotein gene deleted pseudotyped with the N2C glycoprotein (SAD-RV(ΔG)-N2C(G)) shows strong neuro-tropism in cell culture, but its in vivo efficiency for retrograde gene transduction and neuro-tropism have not been systematically characterized. We compared these features in different mouse brain regions for SAD-RV-N2C(G) and two other widely-used retrograde tracers, SAD-RV(ΔG)-B19(G) and rAAV2-retro. We found that SAD-RV(ΔG)-N2C(G) enhanced the infection efficiency of long-projecting neurons by ~10 times but with very similar neuro-tropism, compared with SAD-RV(ΔG)-B19(G). On the other hand, SAD-RV(ΔG)-N2C(G) had an infection efficiency comparable with rAAV2-retro, but a more restricted diffusion range, and broader tropism to different types and regions of long-projecting neuronal populations. These results demonstrate that SAD-RV(ΔG)-N2C(G) can serve as an effective retrograde vector for studying neuronal circuits.
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http://dx.doi.org/10.1007/s12264-019-00423-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056755PMC
March 2020

Influence of Different Pretreatments on the Structure and Hydrolysis Behavior of Bamboo: A Comparative Study.

Materials (Basel) 2019 Aug 12;12(16). Epub 2019 Aug 12.

Natural Resources Institute Finland (Luke), Production Systems, Tietotie 2, FI-02150 Espoo, Finland.

In the present study, three pretreatments of sodium hydroxide (NaOH), sulfuric acid (HSO), and glycerin were employed with bamboo fibers at two different temperatures of 117 °C and 135 °C, respectively. The chemical composition and structural characterization of the pretreated bamboo fibers were comparatively studied using spectroscopic and wet chemistry methods. Furthermore, the comparative hydrolysis behaviors of pretreated bamboo were studied due to the synergistic interaction between cellulases and xylanase. The NaOH treatment increased the holocellulose contents to 87.4%, and the mean diameter of the cellulose fibers decreased from 50 ± 5 µm (raw fiber bundles) to 5 ± 2 µm. The lignin content and the degree of cellulose polymerization both decreased, while the crystallinity index of cellulose and thermostability increased. The hydrolysis yields of NaOH pretreated bamboo at 135 °C increased from 84.2% to 98.1% after a supplement of 0.5 cellulose to 1 mg protein/g dry xylan. The NaOH pretreatment achieved optimal enzymatic digestibility, particularly at higher temperatures as indicated by the results.
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http://dx.doi.org/10.3390/ma12162570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720690PMC
August 2019

Life Cycle Assessment of Plywood Manufacturing Process in China.

Int J Environ Res Public Health 2019 06 8;16(11). Epub 2019 Jun 8.

Natural Resources Institute Finland (Luke), Production Systems, Tietotie 2, FI-02150 Espoo, Finland.

Life cycle assessment (LCA) has been an important issue in the development of a circular economy. LCA is used to identify environmental impacts and hotspots associated with plywood manufacturing. Based on our results and a literature review of LCA studies involving plywood, a sustainable and environmentally friendly scenario was proposed for the plywood processing industry to improve environmental performance and sustainability. This study covers the life cycle of plywood production from a cradle-to-gate perspective, including raw material preparation and plywood manufacturing and processing to analysis of environment impacts and hotspots. Analysis of abiotic depletion (ADP), acidification effect (AP), primary energy depletion (PED), freshwater eutrophication (EP), global warming potential (GWP), and particulate matter (RI) were selected as major impact categories in this study. All data were obtained from on-site measurements (plywood production) and investigations of the Eco-invent database and CLCD database (upstream data of materials and energy). These data can be ignored when environmental contributions comprise less than 0.001% of environmental impact and auxiliary material quality is less than 0.01% of total raw material consumption. An eco-design strategy with eco-alternatives was proposed: pyrolysis bio-oil can be used to produce green resin to replace traditional phenolic formaldehyde (PF) resin to decrease the impacts of GWP, PED, AP, PM, and especially ADP and EP. A new technology of gluing green wood was used to replace conventional plywood production technology; wood waste could undergo a gasification process to produce resultant gas rather than combusting. Plywood was also compared with other wood-based panels in China to identify additional scenarios to improve environmental sustainability.
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http://dx.doi.org/10.3390/ijerph16112037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603926PMC
June 2019

Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization.

Mucosal Immunol 2019 07 13;12(4):888-896. Epub 2019 May 13.

Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.
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http://dx.doi.org/10.1038/s41385-019-0169-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746522PMC
July 2019

Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated osteogenic pathway.

J Thorac Cardiovasc Surg 2019 08 15;158(2):408-417.e2. Epub 2018 Nov 15.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, China. Electronic address:

Objective: Aortic valve (AoV) calcification occurs via a pathophysiologic process that includes osteoblastic differentiation of valvular interstitial cells (VICs). Histone deacetylases (HDACs) have been shown to be involved in the pathogenesis of vascular diseases. Here, we investigated the role of HDAC6 in AoV calcification.

Methods: AoV cusps from patients with aortic stenosis (n = 7) and normal controls (n = 7) were subjected to determination of calcified nodules and HDAC6 expression. Human VICs were cultured in osteogenic media and treated with 10 uM tubacin or HDAC6 small interfering RNA silencing to inhibit HDAC6. Treatment with 100 uM tauroursodeoxycholic acid was used to suppress endoplasmic reticulum stress. Activating transcription factor 4 (ATF4) small interfering RNA was used to knock down ATF4. Alizarin red staining was used to evaluate calcified nodules formation of VICs cultured with osteogenic media for 14 days.

Results: HDAC6 expression was significantly reduced in AoV tissue of patients with aortic stenosis compared with controls. Tubacin treatment or HDAC6 silencing markedly promoted osteoblastic differentiation accompanied by endoplasmic reticulum stress activation in VICs. The HDAC6 inhibition-induced osteogenic pathway was mediated by endoplasmic reticulum stress/ATF4 pathway as indicated by tauroursodeoxycholic acid pretreatment or ATF4 silencing. Finally, alizarin red staining showed that HDAC6 inhibition promoted osteoblastic differentiation of VICs, which could be suppressed by tauroursodeoxycholic acid.

Conclusions: HDAC6 inhibition promotes AoV calcification via an endoplasmic reticulum stress/ATF4-mediated osteogenic pathway. HDAC6 may be a novel target for AoV calcification prevention and treatment.
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http://dx.doi.org/10.1016/j.jtcvs.2018.10.136DOI Listing
August 2019

Increased myocardial stiffness activates cardiac microvascular endothelial cell via VEGF paracrine signaling in cardiac hypertrophy.

J Mol Cell Cardiol 2018 09 20;122:140-151. Epub 2018 Aug 20.

Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China. Electronic address:

When the heart is subjected to an increased workload, mechanical stretch together with neurohumoral stimuli activate the "fetal gene program" and induce cardiac hypertrophy to optimize output. Due to a lack of effective methods/models to quantify and modulate cardiac mechanical properties, the connection between these properties and the development of cardiac hypertrophy remains largely unexplored. Here, we utilized an atomic force microscope (AFM) to directly measure the elastic modulus of the hypertrophic myocardium induced by pressure overload. Additionally, we investigated the effects of extracellular elasticity on angiogenesis, which provides blood and nutrition to support cardiomyocyte hypertrophic growth in this process. In response to pressure overload, the myocardium rapidly developed hypertrophy and correspondingly demonstrated a high elastic modulus property. This mechanical feature correlated with enhanced angiogenesis. Mechanistically, we found that a high elastic modulus promoted cultured cardiomyocytes to synthesize and paracrine vascular endothelial growth factor (VEGF) to activate cardiac microvascular endothelial cells. Further analysis showed that the increased elastic modulus enhanced the interaction between Talin1 and integrin β1 to activate the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1α (Hif-1α) pathway, which contributed to VEGF production. Thus, our study revealed a critical role of the elastic modulus in regulating angiogenesis during the development of cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.yjmcc.2018.08.014DOI Listing
September 2018

Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase.

Circ Res 2018 05 18;122(11):1532-1544. Epub 2018 Apr 18.

From the Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Rationale: To date, our understanding of the role of HO-1 (heme oxygenase-1) in inflammatory diseases has mostly been limited to its catalytic function and the potential for its heme-related catabolic products to suppress inflammation and oxidative stress. Whether and how HO-1 in macrophages plays a role in the development of septic cardiac dysfunction has never been explored.

Objective: Here, we investigated the role of macrophage-derived HO-1 in septic cardiac dysfunction.

Methods And Results: Intraperitoneal injection of lipopolysaccharide significantly activated HO-1 expression in cardiac infiltrated macrophages. Surprisingly, we found that myeloid conditional HO-1 deletion in mice evoked resistance to lipopolysaccharide-triggered septic cardiac dysfunction and lethality in vivo, which was accompanied by reduced cardiomyocyte apoptosis in the septic hearts and decreased peroxynitrite production and iNOS (inducible NO synthase) in the cardiac infiltrated macrophages, whereas proinflammatory cytokine production and macrophage infiltration were unaltered. We further demonstrated that HO-1 suppression abolished the lipopolysaccharide-induced iNOS protein rather than mRNA expression in macrophages. Moreover, we confirmed that the inhibition of HO-1 promoted iNOS degradation through a lysosomal rather than proteasomal pathway in macrophages. Suppression of the lysosomal degradation of iNOS by bafilomycin A1 drove septic cardiac dysfunction in myeloid HO-1-deficient mice. Mechanistically, we demonstrated that HO-1 interacted with iNOS at the flavin mononucleotide domain, which further prevented iNOS conjugation with LC3 (light chain 3) and subsequent lysosomal degradation in macrophages. These effects were independent of HO-1's catabolic products: ferrous ion, carbon monoxide, and bilirubin.

Conclusions: Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312910DOI Listing
May 2018

Pursuing sustainable productivity with millions of smallholder farmers.

Nature 2018 03 7;555(7696):363-366. Epub 2018 Mar 7.

Institute of Agricultural Resources and Environment, Hebei Academy of Agriculture and Forestry Sciences, Shijiazhuang 050051, China.

Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook.
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http://dx.doi.org/10.1038/nature25785DOI Listing
March 2018

Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis.

PLoS Pathog 2018 01 23;14(1):e1006872. Epub 2018 Jan 23.

Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Cardiovascular Key Lab of Zhejiang Province, Hangzhou, Zhejiang, China.

Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.
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http://dx.doi.org/10.1371/journal.ppat.1006872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809100PMC
January 2018

Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo.

Aging Cell 2017 12 10;16(6):1334-1341. Epub 2017 Sep 10.

Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Aortic valve (AoV) calcification is common in aged populations. Its subsequent aortic stenosis has been linked with increased morbidity, but still has no effective pharmacological intervention. Our previous data show endoplasmic reticulum (ER) stress is involved in AoV calcification. Here, we investigated whether deficiency of ER stress downstream effector CCAAT/enhancer-binding protein homology protein (CHOP) may prevent development of AoV calcification. AoV calcification was evaluated in Apoe mice (n = 10) or in mice with dual deficiencies of ApoE and CHOP (Apoe CHOP , n = 10) fed with Western diet for 24 weeks. Histological and echocardiographic analysis showed that genetic ablation of CHOP attenuated AoV calcification, pro-calcification signaling activation, and apoptosis in the leaflets of Apoe mice. In cultured human aortic valvular interstitial cells (VIC), we found oxidized low-density lipoprotein (oxLDL) promoted apoptosis and osteoblastic differentiation of VIC via CHOP activation. Using conditioned media (CM) from oxLDL-treated VIC, we further identified that oxLDL triggered osteoblastic differentiation of VIC via paracrine pathway, while depletion of apoptotic bodies (ABs) in CM suppressed the effect. CM from oxLDL-exposed CHOP-silenced cells prevented osteoblastic differentiation of VIC, while depletion of ABs did not further enhance this protective effect. Overall, our study indicates that CHOP deficiency protects against Western diet-induced AoV calcification in Apoe mice. CHOP deficiency prevents oxLDL-induced VIC osteoblastic differentiation via preventing VIC-derived ABs releasing.
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http://dx.doi.org/10.1111/acel.12674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676062PMC
December 2017

EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling.

Circ Res 2017 Sep 25;121(6):617-627. Epub 2017 Jul 25.

From the Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (S.-a.S., D.Y., Y.W., W.Z., Z.C., J.S., Z.F., Y.W., L.J., Y.W., J.-a.W., M.X.); and Cardiovascular Division, King's College London BHF Center, United Kingdom (Y.X.).

Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified.

Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process.

Methods And Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil-coil domain and DNA-binding domain of Stat3 mediated the interaction.

Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311045DOI Listing
September 2017

A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization.

Circ Res 2016 Mar 19;118(6):970-83. Epub 2016 Jan 19.

From the Department of Cardiology (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J. L., J.Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.), Department of Cardiovascular Surgery (H.C., M.K.), Department of Anesthesiology (F.Z., Q.C.), Department of Radiology, (J.S., Qian Li), Department of Nuclear Medicine (H.Z.), and Department of Ultrasonography (Q.Y., L.Y.), Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J.L., J. Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.); Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China (J.C.); and Department of Biomedical Engineering, University of Alabama at Birmingham (J. Zhang).

Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell-based myocardial therapy are needed.

Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation.

Methods And Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×10(7) cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells-treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications.

Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.307516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894788PMC
March 2016

TAB3 overexpression promotes cell proliferation in non-small cell lung cancer and mediates chemoresistance to CDDP in A549 cells via the NF-κB pathway.

Tumour Biol 2016 Mar 17;37(3):3851-61. Epub 2015 Oct 17.

Jiangsu Province Key Laboratory for Inflammation and Molecular Target, Medical College, Nantong University, Nantong, 226001, Jiangsu, China.

Transforming growth factor-activated kinase 1 (TAK1)-binding protein 3 (TAB3) is essential for the activation of the nuclear factor kappa B (NF-κB) pathway and has important roles in cell survival. However, the contribution of TAB3 to non-small cell lung cancer (NSCLC) remains elusive. In the present study, Western blotting and immunohistochemistry assays demonstrated that TAB3 expression was frequently increased in NSCLC tissues and cells. In addition, chi-square test and Kaplan-Meier analysis revealed that upregulation of TAB3 expression correlated with a more invasive tumor phenotype and poor prognosis. In addition, a series of experiments, including serum starvation-refeeding experiment and TAB3-siRNA transfection assay, showed that TAB3 expression promoted NSCLC cell proliferation. Furthermore, the effect of TAB3 expression on the sensitivity to cis-diamminedichloroplatinum (CDDP) and possible signaling transduction pathways was investigated. When the expression of TAB3 was inhibited by siRNA transfection, the sensitivity to CDDP was enhanced. Moreover, it showed that downregulation of TAB3 enhanced CDDP-induced A549 cell apoptosis through the inhibition of the NF-κB pathway. These results suggest that TAB3 plays a critical role in NSCLC progression and chemoresistance and that TAB3 depletion may be a promising approach to lung cancer therapy.
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http://dx.doi.org/10.1007/s13277-015-3896-yDOI Listing
March 2016

Upregulated expression of ILF2 in non-small cell lung cancer is associated with tumor cell proliferation and poor prognosis.

J Mol Histol 2015 Oct 10;46(4-5):325-35. Epub 2015 Jun 10.

Department of Oncology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.

ILF2 (NF45) is a sequence-specific DNA binding protein that is involved in mitosis control, transcriptional regulation, DNA breaks repair, microRNA processing and viral replication. In the present study, we aim to investigate the potential role of ILF2 in the progression of non-small cell lung cancer (NSCLC). Western blot analysis indicated that ILF2 was up-regulated in NSCLC tissues, compared with adjacent non-tumorous ones. Furthermore, immunohistochemistry analysis showed that the expression of ILF2 was correlated with histological differentiation, clinical stage and Ki-67 expression in NSCLC specimens. In addition, using Kaplan-Meier survival analysis, we found that high expression of ILF2 predicted poor outcome in NSCLC patients. Furthermore, we showed that up-regulated expression of ILF2 might play a regulatory role in the proliferation of NSCLC cells using serum starvation and release assay. Moreover, knockdown of ILF2 inhibited cell proliferation and cell cycle progress of NSCLC cells. In conclusion, our results indicated that ILF2 was involved in the pathogenesis of NSCLC and might be a potential target for NSCLC therapy.
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http://dx.doi.org/10.1007/s10735-015-9624-5DOI Listing
October 2015

Evaluation of the yield and nitrogen use efficiency of the dominant maize hybrids grown in North and Northeast China.

Sci China Life Sci 2013 Jun 16;56(6):552-60. Epub 2013 Mar 16.

Key Laboratory of Plant-Soil Interaction, Ministry of Education, College of Resources and Environmental Science, China Agricultural University, Beijing 100193, China.

Breeding high-yielding and nutrient-efficient cultivars is one strategy to simultaneously resolve the problems of food security, resource shortage, and environmental pollution. However, the potential increased yield and reduction in fertilizer input achievable by using high-yielding and nutrient-efficient cultivars is unclear. In the present study, we evaluated the yield and nitrogen use efficiency (NUE) of 40 commercial maize hybrids at five locations in North and Northeast China in 2008 and 2009. The effect of interaction between genotype and nitrogen (N) input on maize yield was significant when the yield reduction under low-N treatment was 25%-60%. Based on the average yields achieved with high or low N application, the tested cultivars were classified into four types based on their NUE: efficient-efficient (EE) were efficient under both low and high N inputs, high-N efficient (HNE) under only high N input, low-N efficient (LNE) under only low N input, and nonefficient-nonefficient under neither low nor high N inputs. Under high N application, EE and HNE cultivars could potentially increase maize yield by 8%-10% and reduce N input by 16%-21%. Under low N application, LNE cultivars could potentially increase maize yield by 12%. We concluded that breeding for N-efficient cultivars is a feasible strategy to increase maize yield and/or reduce N input.
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http://dx.doi.org/10.1007/s11427-013-4462-8DOI Listing
June 2013

Protective effects of total flavonoids from Epimedium on the male mouse reproductive system against cyclophosphamide-induced oxidative injury by up-regulating the expressions of SOD3 and GPX1.

Phytother Res 2014 Jan 12;28(1):88-97. Epub 2013 Mar 12.

Medical College of China Three Gorges University, Yichang, P. R. China.

Total flavonoids of Epimedium (TFE) is the main active composition of Epimedium that has been used to treat male reproductive problems. The present aim was to investigate the protective effects of TFE on male mice reproductive system against cyclophosphamide (CP)-induced oxidative injury. The animals were treated with CP to make testicular injury model and the protective effects of TFE were observed. In the CP-treated group, testicular and epididymal weights, sperm count and motility significantly decreased relative to the control group (P < 0.05 and P < 0.01, respectively). Compared with the CP-treated group, TFE (200 and 400 mg/kg) treated mice increased testicular weights by 21.6% and 28.4% (P < 0.05), sperm counts by 81.7% and 148.3% (P < 0.01) and sperm motility by 47.2% and 61.3% (P < 0.01). Meanwhile, the CP-treated group showed enhancement of lipid peroxidation leading to testicular reproductive toxicity. TFE restored these oxidative damages by up-regulating the expression of antioxidant enzymes, especially SOD3 and GPX1. TUNEL assay and histopathological observations provided supportive evidence for above results, and when the dose of TFE increased, the aforesaid improvement became more and more strong. These results demonstrated that TFE exerted beneficially protective effects on the structural and functional damage of male mice reproductive system and reduced apoptosis in spermatogenic cells by inhibiting CP-induced oxidative stress.
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http://dx.doi.org/10.1002/ptr.4956DOI Listing
January 2014
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