Publications by authors named "Sheng Song"

62 Publications

Isolation and Characterization of Shiga Toxin-Producing from Retail Beef Samples from Eight Provinces in China.

Foodborne Pathog Dis 2021 08;18(8):616-625

Department of Food Science, College of Food Science, Southwest University, Chongqing, China.

While Shiga toxin-producing (STEC) is a major foodborne pathogen worldwide, data on the molecular and phylogenetic properties of STEC isolates from retail beef samples in China remain scant. Fresh retail beef samples ( = 1062) were collected from eight provinces, and STEC isolates were recovered and characterized. PCR data showed that more than 50% of the samples were positive, and 82 STEC isolates were recovered from 14.8% (79/535) -positive enriched broths. In contrast, all ciprofloxacin resistant isolates ( = 19) and 13 cefotaxime (CTX) resistant isolates were positive and belonged to three serotypes: O111:H8, O26:H11, or O157:H7. Point mutations in quinolone resistance-determining regions and plasmid-mediated quinolone resistance determinants were identified in 16 and 20 isolates, respectively. and a point mutation (C-42T) in promoter were detected in 15 and 8 of the CTX resistant isolates, respectively. In addition, macrolide resistance gene was identified in eight azithromycin resistant O111:H8 isolates and one O26:H11 isolate. Single nucleotide polymorphism analysis demonstrated that the O26 and O157 isolates had multiple origins, but the O111 isolates were closely related. Taken together, our data demonstrated that several sequence types associated with hemolytic uremic syndrome from the retail beef samples in China had developed into dangerous multidrug resistant pathogens. The resistant phenotype can facilitate their transmission among the farm animals and human beings when there is an antimicrobial selective pressure.
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http://dx.doi.org/10.1089/fpd.2021.0005DOI Listing
August 2021

Improvement of 3D Ultrasound Spine Imaging technique using Fast Reconstruction Algorithm.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Jun 9;PP. Epub 2021 Jun 9.

Three-dimensional (3D) freehand ultrasound (US) imaging has been applied to the investigation of spine deformity. However, it is a challenge for the current 3D imaging reconstruction algorithms to achieve a balance between image quality and computation time. The objectives of this paper are to implement a new fast reconstruction algorithm which can fulfill the request of immediate demonstration and processing for high-quality 3D spine imaging, and to evaluate the reliability and accuracy of scoliotic curvature measurement when using the algorithm. The Fast Dot-Projection (FDP) algorithm was applied for Voxel-based Nearest Neighbor (VNN), Multiple Plane Interpolation (MPI) and Pixel Nearest Neighbor (PNN) protocols to reduce the reconstruction time. The 3D image volume was reconstructed from the data sets acquired from scoliotic subjects. The computational cost, image characteristics and statistical analyses of curve measurements were compared and evaluated among different reconstruction protocols. The results illustrated that the 3D spine images using the FDP-MPI4 algorithm showed higher brightness (20%), contrast (14%) and SNR (26%) than FDP-VNN. The measurement performed by trainee rater exhibited significant improvement on measurement reliability and accuracy using FDP-MPI4 in comparison with FDP-VNN (p < 0.01), and the ICC of inter-rater measurement increased from 0.88 to 0.96. The FDP-PNN method could acquire and reconstruct spine images simultaneously and present the results in 1-2 minutes, which showed the potential to provide the approximate real-time visualization for the fast screening.
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http://dx.doi.org/10.1109/TUFFC.2021.3087712DOI Listing
June 2021

Role of microRNA-15a-5p/Sox9/NF-κB axis in inflammatory factors and apoptosis of murine nucleus pulposus cells in intervertebral disc degeneration.

Life Sci 2021 Jul 26;277:119408. Epub 2021 Mar 26.

Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi 214000, Jiangsu, China. Electronic address:

Objective: MicroRNAs are well-established players in post-transcriptional gene modulation. We aim to explore the role of microRNA-15a-5p (miR-15a-5p)/sex determining region Y-box 9 (Sox9)/nuclear factor-κB (NF-κB) axis in inflammation and apoptosis of murine nucleus pulposus cells (NPCs) in intervertebral disc degeneration (IVDD).

Methods: Expression levels of miR-15a-5p and Sox9 in disc tissues from IVDD patients were determined. The IVDD mouse models were established by disc puncture, and the modeled mice were accordingly injected with miR-15a-5p antagomir and/or overexpressed Sox9 plasmid, or their negative controls. Then, the expression of miR-15a-5p, Sox9 and p-p65, pathological changes and the apoptosis of NPCs in IVDD mouse intervertebral disc tissues were measured. The NPCs were isolated and cultured, which were then transfected with miR-15a-5p inhibitor, overexpressed or silenced Sox9 plasmids, or the NCs. Next, the expression of miR-15a-5p and Sox9, apoptosis, proliferation and cell cycle distribution of NPCs, and the contents of inflammatory factors in the NPCs were evaluated.

Results: MiR-15a-5p expression was increased while Sox9 expression was reduced in intervertebral disc tissues from IVDD patients and mice. Mouse NPCs were successfully isolated. The down-regulated miR-15a-5p could elevate Sox9 to activate p-p65 expression, suppress NPC apoptosis and inflammatory factor contents, promote proliferation of NPCs, and arrest the NPCs at S and G2/M phases. However, these effects could be reversed by silencing Sox9.

Conclusion: Reduction of miR-15a-5p elevated Sox9 to inhibit the inflammatory response and apoptosis of NPCs in IVDD mice through the NF-κB pathway. This study may be helpful for IVDD treatment.
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http://dx.doi.org/10.1016/j.lfs.2021.119408DOI Listing
July 2021

Phenotypical evidence of effective amelioration of ammonium-inhibited plant (root) growth by exogenous low urea.

J Plant Physiol 2020 Dec 14;255:153306. Epub 2020 Oct 14.

College of Resources and Environmental Sciences, Key Lab of Plant-Soil Interaction, MOE, Centre for Resources, Environment and Food Security, China Agricultural University, Beijing 100193, China. Electronic address:

Ammonium and nitrate are major soil inorganic-nitrogen sources for plant growth, but many species cultivated with even low millimolar NH as a sole N form display a growth retardation. To date, critical biological components and applicable approaches involved in the effective enhancement of NH tolerance remain to be thoroughly explored. Here, we report phenotypical traits of urea-dependent improvement of NH-suppressed plant/root growth. Urea at 0.1 mM was sufficient to remarkably stimulate NH (3 mM)-fed cotton growth, showing a 2.5∼4-fold increase in shoot- and root-biomass and total root-length, 20 % higher GS activity, 18 % less NH-accumulation in roots, and a comparable plant total-N content compared to the control, implying a novel role for urea in cotton NHdetoxification. A similar phenomenon was observed in tobacco and rice. Moreover, comparisons between twelve NH-grown Arabidopsis accessions revealed a great degree of natural variation in their root-growth response to low urea, with WAR and Blh-1 exhibiting the most significant increase in primary- and lateral-root length and numbers, and Sav-0 and Edi-0 being the most insensitive. Such phenotypical evidence suggests a common ability of plants to accommodate NH-stress by responding to exogenous urea, providing a novel aspect for further understanding the process of urea-dependent plant NH tolerance.
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http://dx.doi.org/10.1016/j.jplph.2020.153306DOI Listing
December 2020

Automatic Skull Stripping of Rat and Mouse Brain MRI Data Using U-Net.

Front Neurosci 2020 7;14:568614. Epub 2020 Oct 7.

Center for Animal Magnetic Resonance Imaging, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Accurate removal of magnetic resonance imaging (MRI) signal outside the brain, a.k.a., skull stripping, is a key step in the brain image pre-processing pipelines. In rodents, this is mostly achieved by manually editing a brain mask, which is time-consuming and operator dependent. Automating this step is particularly challenging in rodents as compared to humans, because of differences in brain/scalp tissue geometry, image resolution with respect to brain-scalp distance, and tissue contrast around the skull. In this study, we proposed a deep-learning-based framework, U-Net, to automatically identify the rodent brain boundaries in MR images. The U-Net method is robust against inter-subject variability and eliminates operator dependence. To benchmark the efficiency of this method, we trained and validated our model using both in-house collected and publicly available datasets. In comparison to current state-of-the-art methods, our approach achieved superior averaged Dice similarity coefficient to ground truth T2-weighted rapid acquisition with relaxation enhancement and T2-weighted echo planar imaging data in both rats and mice (all < 0.05), demonstrating robust performance of our approach across various MRI protocols.
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http://dx.doi.org/10.3389/fnins.2020.568614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575753PMC
October 2020

Evidence that exogenous urea acts as a potent cue to alleviate ammonium-inhibition of root system growth of cotton plant (Gossypium hirsutum).

Physiol Plant 2021 Jan 29;171(1):137-150. Epub 2020 Oct 29.

College of Resources and Environmental Sciences, Key Lab of Plant-Soil Interaction, MOE, Centre for Resources, Environment and Food Security, China Agricultural University, Beijing, China.

Many plants grown with low-millimolar concentration of NH as a sole nitrogen source develop NH -toxicity symptoms. To date, crucial molecular identities and a practical approach involved in the improvement of plant NH -tolerance remain largely unknown. By phenotyping of upland cotton grown on varied nitrogen forms, we came across a phenomenon that caused sub-millimolar concentrations of urea (e.g., up 50 μM) to repress the growth inhibition of roots and whole plant cultivated in a NH -containing nutrient solution. A growth-recovery assay revealed that the relief in NH -inhibited growth required only a short-term exposure (≧12 h) of the roots to urea, implying that urea could elicit an internal signaling and be involved in antagonizing NH -sensitivity. Intriguingly, split-root experiments demonstrated that low urea occurrence in one root-half could efficaciously stimulate not only supplied root but also the root-half grown in NH -solution without urea, indicating the existence of urea-triggered local and systemic long-distance signaling. In the split-root experiment we also observed high arginase activity, strong arginine reduction and remarkable upregulation of polyamine biosynthesis-related genes (ADC1/2, SPDS and SPMS). Therefore, we suggest that external urea might serve as an effective cue (signal molecule) in an arginine-/polyamine-related process for ameliorating NH -suppressed root growth, providing a novel aspect for deeper exploring and understanding plant NH -tolerance.
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http://dx.doi.org/10.1111/ppl.13222DOI Listing
January 2021

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice.

Sci Rep 2020 09 14;10(1):15054. Epub 2020 Sep 14.

Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.

This study examined the genetic mutation and toxicant exposure in producing gut microbiota alteration and neurotoxicity. Homozygous α-synuclein mutant (SNCA) mice that overexpress human A53T protein and littermate wild-type mice received a single injection of LPS (2 mg/kg) or a selective norepinephrine depleting toxin DSP-4 (50 mg/kg), then the motor activity, dopaminergic neuron loss, colon gene expression and gut microbiome were examined 13 months later. LPS and DSP-4 decreased rotarod and wirehang activity, reduced dopaminergic neurons in substantia nigra pars compacta (SNpc), and SNCA mice were more vulnerable. SNCA mice had 1,000-fold higher human SNCA mRNA expression in the gut, and twofold higher gut expression of NADPH oxidase (NOX2) and translocator protein (TSPO). LPS further increased expression of TSPO and IL-6 in SNCA mice. Both LPS and DSP-4 caused microbiome alterations, and SNCA mice were more susceptible. The altered colon microbiome approximated clinical findings in PD patients, characterized by increased abundance of Verrucomicrobiaceae, and decreased abundance of Prevotellaceae, as evidenced by qPCR with 16S rRNA primers. The Firmicutes/Bacteroidetes ratio was increased by LPS in SNCA mice. This study demonstrated a critical role of α-synuclein and toxins interactions in producing gut microbiota disruption, aberrant gut pro-inflammatory gene expression, and dopaminergic neuron loss.
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http://dx.doi.org/10.1038/s41598-020-72202-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490385PMC
September 2020

Mean arterial pressure and arterial stiffness in Japanese population: a secondary analysis based on a cross-sectional study.

Authors:
Song Sheng

Blood Press Monit 2020 Dec;25(6):310-317

Emergency Department, Xiyuan Hospital, China Academy of Chines Medical Sciences, Xi Yuan Cao Chang No. 1, Beijing, China.

Previous researches demonstrate that mean arterial pressure (MAP) is associated with major cardiovascular events, but there are few research on the correlation between MAP and brachial-ankle pulse wave velocity (BaPWV). Thus, the present study is designated to examine the association between MAP and BaPWV. Our study is a cross-sectional study in Japanese. They participated in a medical check-up program which included BaPWV and standardized questionnaires. The main measurements include systolic blood pressure, diastolic blood pressure, BaPWV, ankle-brachial index (ABI), fatty liver diagnosed by ultrasonography, etc. It needs to be emphasized that Fukuda et al. finished the study and their data are used for secondary analysis. MAP is positively related with BaPWV [effect size = 10.4; 95% confidence interval (CI), 9.2-11.6] after adjusting age, sex, BMI, smoking status, alcohol consumption, exercise, glutamyltranspeptidase, alanine aminotransferase, aspartate transaminase, total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein cholesterol (HDL), fatty liver, fasting-blood glucose, uric acid, estimated glomerular filtration rate, and ABI. The nonlinear association is identified between MAP and BaPWV whose inflection point is 94 mmHg. The effect size and 95% CI on the bilateral sides of the inflection point are 8.0 (4.4-11.6) and 14.8 (12.5-17.1), respectively. Subgroup analysis indicates that MAP has a more significantly positive association with BaPWV in ex-smokers, old people (age ≥60), and participants with lower HDL (<40 mg/dL). Consequently, it is practicable for us to roughly predict BaPWV with simple MAP measurement instead of the BaPWV examination.
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http://dx.doi.org/10.1097/MBP.0000000000000471DOI Listing
December 2020

The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging.

iScience 2020 Jul 10;23(7):101255. Epub 2020 Jun 10.

Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.
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http://dx.doi.org/10.1016/j.isci.2020.101255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322077PMC
July 2020

Chronic Manganese Administration with Longer Intervals Between Injections Produced Neurotoxicity and Hepatotoxicity in Rats.

Neurochem Res 2020 Aug 2;45(8):1941-1952. Epub 2020 Jun 2.

School of Public Health, Zunyi Medical University, Zunyi, China.

Subacute exposure to manganese (Mn) produced Parkinson's disease-like syndrome called Manganism. Chronic onset and progression are characteristics of Manganism, therefore, this study aimed to examine Mn toxicity following chronic exposures. Male Sprague-Dawley rats were injected Mn 1 and 5 mg/kg, every 10 days for 150 days (15 injections). Animal body weight and behavioral activities were recorded. At the end of experiments, the brain and liver were collected for morphological and molecular analysis. Chronic Mn exposure did not affect animal body weight gain, but the high dose of Mn treatment caused 20% mortality after 140 days of administration. Motor activity deficits were observed in a dose-dependent manner at 148 days of Mn administration. Immunofluorescence double staining of substantia nigra pars compacta (SNpc) revealed the activation of microglia and loss of dopaminergic neurons. The chronic neuroinflammation mediators TNFα, inflammasome Nlrp3, Fc fragment of IgG receptor IIb, and formyl peptide receptor-1 were increased, implicating chronic Mn-induced neuroinflammation. Chronic Mn exposure also produced liver injury, as evidenced by hepatocyte degeneration with pink, condensed nuclei, indicative of apoptotic lesions. The inflammatory cytokines TNFα, IL-1β, and IL-6 were increased, alone with stress-related genes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 and metallothionein. Hepatic transporters, such as multidrug resistant proteins (Abcc1, Abcc2, and Abcc3) and solute carrier family proteins (Slc30a1, Slc39a8 and Slc39a14) were increased in attempt to eliminate Mn from the liver. In summary, chronic Mn exposure produced neuroinflammation and dopaminergic neuron loss in the brain, but also produced inflammation to the liver, with upregulation of hepatic transporters.
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http://dx.doi.org/10.1007/s11064-020-03059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378106PMC
August 2020

Network Pharmacology-Based Exploration of Synergistic Mechanism of Guanxin II Formula (II) for Coronary Heart Disease.

Chin J Integr Med 2021 Feb 9;27(2):106-114. Epub 2020 May 9.

Emergency Department, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China.

Objective: To study the pharmacological mechanism of Guanxin II formula (II) for treatment of coronary heart disease (CHD).

Methods: A network pharmacology-based method was utilized. First candidate compounds, targets of GX II were collected using PharmMapper, BATMAN-TCM, DrugBank and SwissTargetPrediction, and targets on CHD were mined from GeneCards, DisGenet, DrugBank and GEO. Afterwards, the big hub compounds and targets were chosen in the candidate compounds-direct therapeutic targets on the CHD (C-T) network and the direct therapeutic targets on the CHD (T-D) network. Furthermore, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were performed to identify the enriched terms. Finally, a molecular docking simulation strategy was adopted to verify the binding capacity between the big hub compounds and big hub targets on CHD.

Results: First, 114 candidate compounds were selected with the following criteria: OB⩾30%, DL⩾0.18, and HL ⩾4 h. Then, 1,035 targets of GX II were gathered, while 928 targets on CHD were collected. Afterwards, 196 common targets of compound targets and therapeutic targets on CHD were defined as direct therapeutic targets acting on CHD. In addition, the contribution index (CI) in the C-T network was calculated, and 4 centrality properties, including degree, betweenness, closeness and coreness, in the T-D network, 4 big hub compounds, and 6 big hub targets were eventually chosen. Furthermore, the GO and KEGG analysis indicated that GX II acted on CHD by regulating the reactive oxygen species metabolism, steroid metabolism, lipid metabolism, inflammatory response, proliferation, differentiation and apoptosis. The docking results manifested excellent binding capacity between the 4 big hub compounds and 6 big hub targets on CHD.

Conclusion: This network pharmacology-based exploration revealed that GX II might prevent and inhibit the primary pathological processes of CHD.
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http://dx.doi.org/10.1007/s11655-020-3199-zDOI Listing
February 2021

Near-Infrared Fluorescent and Magnetic Resonance Dual-Imaging Coacervate Nanoprobes for Trypsin Mapping and Targeted Payload Delivery of Malignant Tumors.

ACS Appl Mater Interfaces 2020 Apr 2;12(15):17302-17313. Epub 2020 Apr 2.

The State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.

Trypsin-responsive near-infrared fluorescent (NIRF) and magnetic resonance (MR) dual-imaging composite nanoparticle/polypeptide coacervate nanoprobes with tunable sizes, have been constructed herein via electrostatic interaction-induced self-assembly. Considering the requirements of in vivo metabolism on nanoparticle size, three coacervate nanoprobes with diameters of around 100, 200, and 300 nm were fabricated with a polydispersity of around 0.2. These coacervate nanoprobes consist of FeO magnetic nanoparticles surface-decorated with poly acrylic acid and Cy5.5-modified poly-l-lysine (PLL--Cy5.5) serving as MR imaging and trypsin-responsive substrate/NIRF agents, respectively. The notable fluorescence signal from PLL--Cy5.5 is self-quenched due to the short distances between the fluorescent Cy5.5 molecules after construction of the coacervate nanoprobes. Remarkably, coacervate nanoprobes with a diameter of around 100 nm are selectively disintegrated into fragmented segments upon the hydrolysis of PLL by trypsin, resulting in an 18-fold amplification of the NIRF intensity in comparison with the self-assembled coacervate nanoprobes in the quenched state. Moreover, the MR imaging enhancement is also related to the disintegration of the coacervate nanoprobes. Cellular experiments and in vivo studies demonstrate that the coacervate nanoprobes exhibit remarkable trypsin-sensitive NIRF and MR dual-imaging capabilities and thus have excellent potential to serve as dual-imaging nanoprobes for the efficient mapping of malignant tumors in which trypsin is often overexpressed. In consideration of their excellent capability to enrich charged molecules, the coacervate nanoprobes provide a conceptually novel and promising platform toward in vivo trypsin mapping and controlled delivery of targeted payloads.
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http://dx.doi.org/10.1021/acsami.0c03433DOI Listing
April 2020

Mercury sulfide-containing Hua-Feng-Dan and 70W (Rannasangpei) protect against LPS plus MPTP-induced neurotoxicity and disturbance of gut microbiota in mice.

J Ethnopharmacol 2020 May 24;254:112674. Epub 2020 Feb 24.

Key Lab for Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, 563000, China. Electronic address:

Ethnopharmacological Relevance: Mercury sulfides (HgS) are frequently included in Ayurveda, Tibetan and Chinese medicines to assist the presumed therapeutic effects, but the ethnopharmacology remains elusive. The present study examined the protective effects of α-HgS-containing Hua-Feng-Dan and β-HgS-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) against Parkinson's disease mice induced by lipopolysaccharide (LPS) plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Method: A single injection of LPS (5 mg/kg ip) was given to adult male C57BL/6 mice, and 150 days later, the low dose of MPTP (15 mg/kg, ip, for 4 days) was given to produce the "two-hit" Parkinson's disease model. Together with MPTP treatment, mice were fed with clinically-relevant doses of Hua-Feng-Dan (0.6 g/kg) and 70W (0.2 g/kg) for 35 days. Rotarod test was performed to examine muscle coordination capability. At the end of the experiment, brain was transcardially perfused with paraformaldehyde, the substantia nigra was sectioned for microglia (Iba1 staining) and dopaminergic neuron (THir staining) determination. Colon bacterial DNA was extracted and subjected to qPCR analysis with 16S rRNA probes.

Results: The low-grade, chronic neuroinflammation produced by LPS aggravated MPTP neurotoxicity, as evidenced by decreased motor activity, intensified microglia activation and loss of dopaminergic neurons. Both Hua-Feng-Dan and 70W increased rotarod activity and ameliorated the pathological lesions in the brain. In gut microbiomes examined, LPS plus MPTP increased Verrucomicrobiaceae, Methanobacteriaceae, Pronicromonosporaceae, and Clostridaceae species were attenuated by Hua-Feng-Dan and 70W.

Conclusions: α-HgS-containing Hua-Feng-Dan and β-HgS-containing 70W at clinical doses protected against chronic LPS plus MPTP-induced toxicity to the brain and gut, suggesting HgS-containing traditional medicines could target gut microbiota as a mechanism of their therapeutic effects.
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http://dx.doi.org/10.1016/j.jep.2020.112674DOI Listing
May 2020

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration.

J Neuroinflammation 2020 Feb 18;17(1):64. Epub 2020 Feb 18.

Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.

Background: Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson's disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.

Methods: C57BL/6 J, NLRP3, and IL-1R1 mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation and α-synuclein phosphorylation.

Results: LPS-elicited initial increases in mouse brain mRNA levels of TNFα, IL-6, IL-1β, and MCP-1, and nigral microglial activation were not dose-related. By contrast, the delayed increase in brain mature IL-1β levels was dependent on LPS doses and protracted nigral microglial activation was only observed in high dose of LPS-treated mice. LPS-elicited increase in brain mature IL-1β but not IL-1α level was NLRP3-dependent. After high dose LPS treatment, deficiency of NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation. Genetic or pharmacological inhibition of the NLRP3-IL-1β axis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including MHC-II, NOX2, and Mac1, and protected dopaminergic neurons. Ten months after LPS-elicited severe endotoxemia, nigral persisted microglial activation, elevated nitrosylated proteins and phosphorylated α-synuclein, and significant neuronal degeneration developed in wild-type mice but not in NLRP3 or IL-1R1 mice.

Conclusions: This study uncovers a novel role of the NLRP3-IL-1β signaling pathway in gauging the severity of sepsis-associated inflammation and determining whether acute neuroinflammation will resolve or transition to low grade chronic neuroinflammation. These findings also provide novel targets for developing therapy for severe systemic infection-related neurodegeneration.
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http://dx.doi.org/10.1186/s12974-020-1728-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029475PMC
February 2020

Locus coeruleus neurons are most sensitive to chronic neuroinflammation-induced neurodegeneration.

Brain Behav Immun 2020 07 7;87:359-368. Epub 2020 Jan 7.

Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.

Parkinson's disease (PD) develops over decades through spatiotemporal stages that ascend from the brainstem to the forebrain. The mechanism behind this caudo-rostral neurodegeneration remains largely undefined. In unraveling this phenomenon, we recently developed a lipopolysaccharide (LPS)-elicited chronic neuroinflammatory mouse model that displays sequential losses of neurons in brainstem, substantia nigra, hippocampus and cortex. In this study, we aimed to investigate the mechanisms of caudo-rostral neurodegeneration and focused our efforts on the earliest neurodegeneration of vulnerable noradrenergic locus coeruleus (NE-LC) neurons in the brainstem. We found that compared with neurons in other brain regions, NE-LC neurons in untreated mice displayed high levels of mitochondrial oxidative stress that was severely exacerbated in the presence of LPS-elicited chronic neuroinflammation. In agreement, NE-LC neurons in LPS-treated mice displayed early reduction of complex IV expression and mitochondrial swelling and loss of cristae. Mechanistically, the activation of the superoxide-generating enzyme NADPH oxidase (NOX2) on NE-LC neurons was essential for their heightened vulnerability during chronic neuroinflammation. LPS induced early and high expressions of NOX2 in NE-LC neurons. Genetic or pharmacological inactivation of NOX2 markedly reduced mitochondrial oxidative stress and dysfunction in LPS-treated mice. Furthermore, inhibition of NOX2 significantly ameliorated LPS-induced NE-LC neurodegeneration. More importantly, post-treatment with NOX2 inhibitor diphenyleneiodonium when NE-LC neurodegeneration had already begun, still showed high efficacy in protecting NE-LC neurons from degeneration in LPS-treated mice. This study strongly supports that chronic neuroinflammation and NOX2 expression among vulnerable neuronal populations contribute to caudo-rostral degeneration in PD.
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http://dx.doi.org/10.1016/j.bbi.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316605PMC
July 2020

Noradrenergic dysfunction accelerates LPS-elicited inflammation-related ascending sequential neurodegeneration and deficits in non-motor/motor functions.

Brain Behav Immun 2019 10 24;81:374-387. Epub 2019 Jun 24.

Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Electronic address:

The loss of central norepinephrine (NE) released by neurons of the locus coeruleus (LC) occurs with aging, and is thought to be an important factor in producing the many of the nonmotor symptoms and exacerbating the degenerative process in animal models of Parkinson's disease (PD). We hypothesize that selectively depleting noradrenergic LC neurons prior to the induction of chronic neuroinflammation may not only accelerate the rate of progressive neurodegeneration throughout the brain, but may exacerbate nonmotor and motor behavioral phenotypes that recapitulate symptoms of PD. For this reason, we used a "two-hit" mouse model whereby brain NE were initially depleted by DSP-4 one week prior to exposing mice to LPS. We found that pretreatment with DSP-4 potentiated LPS-induced sequential neurodegeneration in SNpc, hippocampus, and motor cortex, but not in VTA and caudate/putamen. Mechanistic study revealed that DSP-4 enhanced LPS-induced microglial activation and subsequently elevated neuronal oxidative stress in affected brain regions in a time-dependent pattern. To further characterize the effects of DSP-4 on non-motor and motor symptoms in the LPS model, physiological and behavioral tests were performed at different time points following injection. Consistent with the enhanced neurodegeneration, DSP-4 accelerated the progressive deficits of non-motor symptoms including hyposmia, constipation, anxiety, sociability, exaggerated startle response and impaired learning. Furthermore, notable decreases of motor functions, including decreased rotarod activity, grip strength, and gait disturbance, were observed in treated mice. In summary, our studies provided not only an accelerated "two-hit" PD model that recapitulates the features of sequential neuron loss and the progression of motor/non-motor symptoms of PD, but also revealed the critical role of early LC noradrenergic neuron damage in the pathogenesis of PD-like symptoms.
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http://dx.doi.org/10.1016/j.bbi.2019.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754798PMC
October 2019

Percutaneous endoscopic lumbar discectomy for LDH via a transforaminal approach versus an interlaminar approach: a meta-analysis.

Orthopade 2020 Apr;49(4):338-349

Department of Orthopedics, Wuxi 9th People's Hospital Affiliated to Soochow University, 999 Liangxilu, 214000, Wuxi, Binghu, China.

Purpose: The aim of this study was to systematically compare the safety and effectiveness of percutaneous endoscopic transforaminal discectomy (PETD) versus percutaneous endoscopic interlaminar discectomy (PEID) for the treatment of lumbar disc herniation (LDH).

Material And Methods: All studies that were performed to compare PETD with PEID to treat LDH and published until 31 August 2017 were acquired through a comprehensive search in various databases. A meta-analysis was performed using the Cochrane Collaboration's RevMan 5.3 software.

Results: A total of 13 trials with 974 cases consisting of 3 randomized controlled trials, 3 prospective studies and 7 retrospective studies were included. The results suggest that patients treated with PEID experienced more significant advantages with shorter operation time, less intraoperative blood loss and less intraoperative fluoroscopy times but more complications than those treated with PETD; however, the two operative approaches did not significantly differ in terms of LDH recurrence, hospital stay, Oswestry disability index (ODI) scores, visual analogue scale (VAS) scores, Japanese Orthopaedic Association (JOA) scores and MacNab criteria at the final follow-up.

Conclusion: Based on the results of this study, although PEID may be superior to PETD in certain ways, some of its advantages have yet to be verified and the two interventions were not significantly different in terms of relief of symptoms and functional recovery. Therefore, PEID would be recommended for treating LDH especially at L5/S1 under certain conditions but a prudent attitude is necessary to choose between the two operative approaches before a large sample and high quality randomized controlled trials have been performed.
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http://dx.doi.org/10.1007/s00132-019-03710-zDOI Listing
April 2020

MiR-1-5p is down-regulated in gallbladder carcinoma and suppresses cell proliferation, migration and invasion by targeting Notch2.

Pathol Res Pract 2019 Jan 22;215(1):200-208. Epub 2018 Oct 22.

Emergency Trauma Surgery, BinZhou Medical University Hospital, Binzhou, Shandong, 256600, China. Electronic address:

Background: Numerous studies have demonstrated that aberrant microRNAs (miRNAs) are involved in tumorigenesis and tumor progression. Nevertheless, the precise role of miR-1-5p in gallbladder carcinoma cell growth and metastasis remains not fully revealed.

Material And Methods: The levels of miR-1-5p were detected in gallbladder carcinoma tissues and cell lines using qRT-PCR method. A series of functional assays, including cell proliferation, colony formation, wound healing and Transwell invasion were conducted using miR-1-5p or miR-1-5p inhibitor transfected cells.

Results: MiR-1-5p was remarkably down-regulated in gallbladder carcinoma tissues and cell lines compared to normal. In addition, over-expression of miR-1-5p markedly suppressed the growth, migration and invasion of gallbladder carcinoma cell. Conversely, down-expression of miR-1-5p facilitated gallbladder carcinoma cell proliferation and aggressiveness. Mechanistic investigations demonstrated that neurogenic locus notch homolog protein 2 (Notch2) was the directly target of miR-1-5p and Notch2 mediated the inhibitory effect of miR-1-5p in gallbladder carcinoma cell growth and aggressiveness.

Conclusion: Our findings demonstrated that miR-1-5p acted as a suppressive miRNA and played vital roles in the growth, migration and invasion of gallbladder carcinoma cell through targeting Notch2.
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http://dx.doi.org/10.1016/j.prp.2018.10.013DOI Listing
January 2019

Molecular identification and functional characterization of GhAMT1.3 in ammonium transport with a high affinity from cotton (Gossypium hirsutum L.).

Physiol Plant 2019 Oct 21;167(2):217-231. Epub 2018 Dec 21.

Shanghai Center for Plant Stress Biology, Institute of Plant Physiology Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.

Ammonium (NH ) represents a primary nitrogen source for many plants, its effective transport into and between tissues and further assimilation in cells determine greatly plant nitrogen use efficiency. However, biological components involved in NH movement in woody plants are unclear. Here, we report kinetic evidence for cotton NH uptake and molecular identification of certain NH transporters (AMTs) from cotton (Gossypium hirustum). A substrate-influx assay using N-isotope revealed that cotton possessed a high-affinity transport system with a K of 58 μM for NH . Sequence analysis showed that GhAMT1.1-1.3 encoded respectively a membrane protein containing 485, 509 or 499 amino acids. Heterologous functionality test demonstrated that GhAMT1.1-1.3 expression mediated NH permeation across the plasma membrane (PM) of yeast and/or Arabidopsis qko-mutant cells, allowing a growth restoration of both mutants on NH . Quantitative PCR measurement showed that GhAMT1.3 was expressed in roots and leaves and markedly up-regulated by N-starvation, repressed by NH resupply and regulated diurnally and age-dependently, suggesting that GhAMT1.3 should be a N-responsive gene. Importantly, GhAMT1.3 expression in Arabidopsis improved plant growth on NH and enhanced total nitrogen accumulation (∼50% more), conforming with the observation of 2-fold more NH absorption by GhAMT1.3-transformed qko plant roots during a 1-h root influx period. Together with its targeting to the PM and saturated transport kinetics with a K of 72 μM for NH , GhAMT1.3 is suggested to be a high-affinity NH permease that may play a significant role in cotton NH acquisition and utilization, adding a new member in the plant AMT family.
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http://dx.doi.org/10.1111/ppl.12882DOI Listing
October 2019

Correction to: Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats.

Neurotox Res 2019 May;35(4):999-1000

National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.

The original version of this article contained mistakes, and the authors would like to correct them. Some parts of the image in Figure 5 were missing. The correct Figure 5 is shown at the next page.
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http://dx.doi.org/10.1007/s12640-018-9982-3DOI Listing
May 2019

Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats.

Neurotox Res 2019 Feb 17;35(2):421-431. Epub 2018 Oct 17.

National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.

A single injection of LPS produced low-grade neuroinflammation leading to Parkinson's disease (PD) in mice several months later. Whether such a phenomenon occurs in rats and whether such low-grade neuroinflammation would aggravate rotenone (ROT) neurotoxicity and disrupts circadian clock gene/protein expressions were examined in this study. Male rats were given two injections of LPS (2.5-7.5 mg/kg), and neuroinflammation and dopamine neuron loss were evident 3 months later. Seven months after a single LPS (5 mg/kg) injection, rats received low doses of ROT (0.5 mg/kg, sc, 5 times/week for 4 weeks) to examine low-grade neuroinflammation on ROT toxicity. LPS plus ROT produced more pronounced non-motor and motor dysfunctions than LPS or ROT alone in behavioral tests, and decreased mitochondrial complex 1 activity, together with aggravated neuroinflammation and neuron loss. The expressions of clock core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock), and neuronal PAS domain protein-2 (Npas2) were decreased in LPS, ROT, and LPS plus ROT groups. The expressions of circadian feedback genes Periods (Per1 and Per2) were also decreased, but Cryptochromes (Cry1 and Cry2) were unaltered. The circadian clock target genes nuclear receptor Rev-Erbα (Nr1d1), and D-box-binding protein (Dbp) expressions were also decreased. Consistent with the transcript levels, circadian clock protein BMAL1, CLOCK, NR1D1, and DBP were also decreased. Thus, LPS-induced chronic low-grade neuroinflammation potentiated ROT neurotoxicity and disrupted circadian clock gene/protein expression, suggesting a role of disrupted circadian in PD development and progression. Graphical Abstract ᅟ.
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http://dx.doi.org/10.1007/s12640-018-9968-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543539PMC
February 2019

Loss of Brain Norepinephrine Elicits Neuroinflammation-Mediated Oxidative Injury and Selective Caudo-Rostral Neurodegeneration.

Mol Neurobiol 2019 Apr 27;56(4):2653-2669. Epub 2018 Jul 27.

Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop F1-01Research Triangle Park, North Carolina, 27709, USA.

Environmental toxicant exposure has been strongly implicated in the pathogenesis of Parkinson's disease (PD). Clinical manifestations of non-motor and motor symptoms in PD stem from decades of progressive neurodegeneration selectively afflicting discrete neuronal populations along a caudo-rostral axis. However, recapitulating this spatiotemporal neurodegenerative pattern in rodents has been unsuccessful. The purpose of this study was to generate such animal PD models and delineate mechanism underlying the ascending neurodegeneration. Neuroinflammation, oxidative stress, and neuronal death in mice brains were measured at different times following a single systemic injection of lipopolysaccharide (LPS). We demonstrate that LPS produced an ascending neurodegeneration that temporally afflicted neurons initially in the locus coeruleus (LC), followed by substantia nigra, and lastly the primary motor cortex and hippocampus. To test the hypothesis that LPS-elicited early loss of noradrenergic LC neurons may underlie this ascending pattern, we used a neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete brain norepinephrine. DSP-4 injection resulted in a time-dependent ascending degenerative pattern similar to that generated by the LPS model. Mechanistic studies revealed that increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX2)-dependent superoxide/reactive oxygen species (ROS) production plays a key role in both LPS- and DSP-4-elicited neurotoxicity. We found that toxin-elicited chronic neuroinflammation, oxidative neuronal injuries, and neurodegeneration were greatly suppressed in mice deficient in NOX2 gene or treated with NOX2-specific inhibitor. Our studies document the first rodent PD model recapturing the ascending neurodegenerative pattern of PD patients and provide convincing evidence that the loss of brain norepinephrine is critical in initiating and maintaining chronic neuroinflammation and the discrete neurodegeneration in PD.
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http://dx.doi.org/10.1007/s12035-018-1235-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348128PMC
April 2019

[Treatment of thoracolumbar burst fractures with short-segment pedicle instrumentation and recombinant human bone morphogenetic protein 2 and allogeneic bone grafting in injured vertebra].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2017 09;31(9):1080-1085

Department of Orthopedics, Wuxi Orthopedic Hospital Affiliated to Soochow University, the Ninth People's Hospital of Wuxi, Wuxi Jiangsu, 214000, P.R.China.

Objective: To investigate the effect of preventing the loss of correction and vertebral defects after thoracolumbar burst fractures treated with recombinant human bone morphogenetic protein 2 (rhBMP-2) and allogeneic bone grafting in injured vertebra uniting short-segment pedicle instrumentation.

Methods: A prospective randomized controlled study was performed in 48 patients with thoracolumbar fracture who were assigned into 2 groups between June 2013 and June 2015. Control group ( =24) received treatment with short-segment pedicle screw instrumentation with allogeneic bone implanting in injured vertebra; intervention group ( =24) received treatment with short-segment pedicle screw instrumentation combining with rhBMP-2 and allogeneic bone grafting in injured vertebra. There was no significant difference in gender, age, injury cause, affected segment, vertebral compression degree, the thoracolumbar injury severity score (TLICS), Frankel grading for neurological symptoms, Cobb angle, compression rate of anterior verterbral height between 2 groups before operation ( >0.05). The Cobb angle, compression rate of anterior vertebral height, intervertebral height changes, and defects in injured vertebra at last follow-up were compared between 2 groups.

Results: All the patients were followed up 21-45 months (mean, 31.3 months). Bone healing was achieved in 2 groups, and there was no significant difference in healing time of fracture between intervention group [(7.6±0.8) months] and control group [(7.5±0.8) months] ( =0.336, =0.740). The Frankel grading of all patients were reached grade E at last follow-up. The Cobb angle and compression rate of anterior verterbral height at 1 week after operation and last follow-up were significantly improved when compared with preoperative ones in 2 groups ( <0.05). There was no significant difference in Cobb angle and compression rate of anterior verterbral height between 2 groups at 1 week after operation ( >0.05), but the above indexes in intervention group were better than those in control group at last follow-up ( <0.05). At last follow-up, there was no significant difference of intervertebral height changes of internal fixation adjacent upper position, injured vertebra adjacent upper position, injured vertebra adjacent lower position, and internal fixation adjacent lower position between 2 groups ( >0.05). Defects in injured vertebra happened in 18 cases (75.0%) in control group and 5 cases (20.8%) in intervention group, showing significant difference ( =14.108, =0.000); and in patients with defects in injured vertebra, bone defect degree was 7.50%±3.61% in control group, and was 2.70%±0.66% in intervention group, showing significant difference ( =6.026, =0.000).

Conclusion: Treating thoracolumbar fractures with short-segment pedicle screw instrumentation with rhBMP-2 and allogeneic bone grafting in injured vertebra can prevent the loss of correction and vertebral defects.
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http://dx.doi.org/10.7507/1002-1892.201703065DOI Listing
September 2017

Short-time dental resin biostability and kinetics of enzymatic degradation.

Acta Biomater 2018 07 9;74:326-333. Epub 2018 May 9.

Volpe Research Center, American Dental Association Foundation, Gaithersburg, MD 20899, USA. Electronic address:

Resin biostability is of critical importance to the durability of methacrylate-based dental resin restorations. Current methods for evaluating biostability take considerable time, from weeks to months, and provide no short-time kinetics of resin degradation. The objective of this study is to develop a more sensitive method to assess resin biostability over short-time spans (hours to days) that will enhance our understanding of biostability and its resin chemistry. Ultra-flat resin films of equimolar urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) are produced through photo-curing between two flat surfaces. Next, metal-covered enclaves and bare-resin channels are generated using stencil lithography to create both degradable and protected (internal reference) regions simultaneously in a single specimen. Resins having three different degrees of vinyl conversion (DC) are compared, and changes of surface roughness and step height in the two regions are monitored by atomic force microscopy (AFM) before and after incubated in enzyme solutions and saline controls. Specimen biostability is ranked based on the topological profile changes when viewed in cross-section before and after enzymatic challenges. In addition, a model is proposed to quantify specimen enzymatic degradation. Based on this model, enzymatic degradation is detected as early as 4 h, and a surge of enzymatic degradation is detected between 4 h and 8 h. The correlation between the DC of resin network and the surge in degradation is discussed. In summary, this new method is effective in ranking biostability and quantifying enzymatic degradation while also reducing labor, time and cost, which lends itself well to materials development and evaluation of dental resins.

Statement Of Significance: We report, for the first time, the short-time kinetics of enzymatic degradation of methacrylate dental resins. A nanotechnology based method is developed to accelerate the evaluation of resin biostability. This new method reduces experimental time from weeks to one or two days, which will significantly reduce the costs of labor and enzymes. It also introduces a corresponding parameter (ΔH) and a three-cause model for ranking biostability, which confirms the correlation of chemical structure (DC) and material performance and opens new opportunities for studying the resin biostability and its impact on dental applications. Overall, this is a new tool for evaluating resin biostability and developing new materials.
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http://dx.doi.org/10.1016/j.actbio.2018.05.009DOI Listing
July 2018

Enhanced expression of SRPK2 contributes to aggressive progression and metastasis in prostate cancer.

Biomed Pharmacother 2018 Jun 26;102:531-538. Epub 2018 Mar 26.

Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou, 510800, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China; Department of Pathology, Department of Urology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Serine/Arginine-Rich Protein-Specific Kinase-2 (SRSF protein kinase-2, SRPK2) is up-regulated in multiple human tumors. However, the expression, function and clinical significance of SRPK2 in prostate cancer (PCa) has not yet been understood. We therefore aimed to determine the association of SRPK2 with tumor progression and metastasis in PCa patients in our present study. The expression of SRPK2 was detected by some public datasets and validated using a clinical tissue microarray (TMA) by immunohistochemistry. The association of SRPK2 expression with various clinicopathological characteristics of PCa patients was subsequently statistically analyzed based on the The Cancer Genome Atlas (TCGA) dataset and clinical TMA. The effects of SRPK2 on cancer cell proliferation, migration, invasion, cell cycle progression, apoptosis and tumor growth were then respectively investigated using in vitro and in vivo experiments. First, public datasets showed that SRPK2 expression was greater in PCa tissues when compared with non-cancerous tissues. Statistical analysis demonstrated that high expression of SRPK2 was significantly correlated with a higher Gleason Score, advanced pathological stage and the presence of tumor metastasis in the TCGA Dataset (all P < 0.01). Similar correlations between SRPK2 and a higher Gleason Score or advanced pathological stage were also identified in the TMA (P < 0.05). Kaplan-Meier curve analyses showed that the biochemical recurrence (BCR)-free time of PCa patients with SRPK2 high expression was shorter than for those with SRPK2 low expression (P < 0.05). Second, cell function experiments in PCa cell lines revealed that enhanced SRPK2 expression could promote cell proliferation, migration, invasion and cell cycle progression but suppress tumor cell apoptosis in vitro. Xenograft experiments showed that SRPK2 promoted tumor growth in vivo. In conclusion, our data demonstrated that SRPK2 may play an important role in the progression and metastasis of PCa, which suggests that it might be a potential therapeutic target for PCa clinical therapy.
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http://dx.doi.org/10.1016/j.biopha.2018.03.079DOI Listing
June 2018

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology.

Cell Rep 2017 Aug;20(9):2169-2183

Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.
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http://dx.doi.org/10.1016/j.celrep.2017.07.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578720PMC
August 2017

Repeated manganese administration produced abnormal expression of circadian clock genes in the hypothalamus and liver of rats.

Neurotoxicology 2017 Sep 13;62:39-45. Epub 2017 May 13.

School of Public Health, Zunyi Medical College, Zunyi 563000, China; Zunyi Medical and Pharmaceutical College, Zunyi 563000, China. Electronic address:

Manganese (Mn) neurotoxicity displays non-motor dysfunction and motor impairment like Parkinson's disease (PD), and is called as Manganism. Circadian disruption is a non-motor symptom found in PD and Manganism. Clock genes are essential to drive and maintain circadian rhythm, but little is known about Mn exposure on circadian clock genes expression. Both the brain and liver are targets of Mn, we hypothesize that repeated Mn administration could affect clock gene expression in the hypothalamus and livers. Male Sprague-Dawley rats were intraperitoneally injected Mn 1mg and 5mg/kg as MnCl·4HO, every other day for 30 days. Mn neurotoxicity was evaluated by behavioral changes and loss of dopaminergic neurons via immunohistochemistry. The expression of circadian clock genes was determined via RT-qPCR. Repeated Mn administration dose-dependently retarded the body weight gain, impaired the rotarod activity, decreased the number of dopaminergic neurons in the substantia nigra, and activated microglia in the brain. Expressions of circadian core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock) and neuronal PAS domain protein2 (Npas2), and clock feedback gene cryptochrome1 (Cry1), period genes (Per1 and Per2) in the hypothalamus and liver were decreased after exposure to Mn in a dose-dependent manner, while expressions of clock-targeted genes nuclear receptor Rev-Erbα (Nr1d1) and D-box-binding protein (Dbp) were increased. Peripheral clock in the liver appears to be more susceptible to Mn-induced abnormal clock gene expression. In summary, repeated Mn administration produced dysregulation of circadian clock gene expressions in both the brain and liver.
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http://dx.doi.org/10.1016/j.neuro.2017.05.007DOI Listing
September 2017

Structural regulation of self-assembled iron oxide/polymer microbubbles towards performance-tunable magnetic resonance/ultrasonic dual imaging agents.

J Colloid Interface Sci 2016 Nov 19;482:95-104. Epub 2016 Jul 19.

The State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China; School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom. Electronic address:

Fe3O4/polymer hybrid microcapsules were prepared via a template-free route which is based on polyamine-salt aggregates (PSAs) self-assembly approach. The measurements of transmission electron microscopy (TEM) indicated that the diameter and shell thickness of the microcapsules could be tuned by varying the experimental conditions, such as the concentration of reactants and evolution time employed during the PSA assembly. The results of vibrating sample magnetometer (VSM) demonstrated that the magnetic nanoparticles content of the synthesized microcapsules was tunable and all samples exhibited superparamagnetic behavior. After filling appropriate perfluorocarbon into the inner cavities of the microcapsules, the biomedical applications of the resultant microbubbles, including ultrasonic imaging (USI) and magnetic resonance imaging (MRI), were studied in vitro. It showed that the synthesized magnetic microbubbles possessed both strong ultrasound contrast enhancement capability and high relaxation rate. The excellent acoustic and magnetic properties of these self-assembled microbubbles ensure that the Fe3O4/polymer hybrid microbubbles have great potential as MRI/USI dual-modality contrast agents.
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http://dx.doi.org/10.1016/j.jcis.2016.07.042DOI Listing
November 2016

Structural characterization, molecular modification and hepatoprotective effect of melanin from Lachnum YM226 on acute alcohol-induced liver injury in mice.

Food Funct 2016 Aug 3;7(8):3617-27. Epub 2016 Aug 3.

School of food science and engineering, Hefei University of Technology, Hefei, 230009, China.

In this paper, the possible structural formula of the intracellular homogeneous melanin of Lachnum YM226 (LM) was concluded based on an elemental assay, ultraviolet-visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and equivalent series resistance (ESR). Meanwhile, a d-glucosamine melanin derivative (GLM) was also prepared and its cytotoxicity was evaluated using the MTT assay. The hepatoprotective effect of LM and GLM was evaluated in an acute alcohol-induced liver injury model. The results showed that pretreatments with LM and GLM markedly decreased subsequent alcohol elicited acute hepatic oxidative and inflammatory stress via improving the activity of antioxidant enzymes (glutathione (GSH), catalase (CAT), glutathione peroxidase (GPX), and total superoxide dismutase (SOD)), reducing hepatic levels of nuclear transcription factor (NF-κB), cytokines related to its activation (interleukin (IL)-6, tumor necrosis factor (TNF)-α and macrophage chemoattractant protein (MCP)-1) and hepatic activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. The protection properties of alcoholic liver injury of GLM were more obvious than that of LM at the same dose. The present findings recommend that LM and GLM may be used as a prototype for the prevention of alcoholic liver injury.
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http://dx.doi.org/10.1039/c6fo00333hDOI Listing
August 2016

[EFFECTIVENESS COMPARISON OF PROXIMAL FEMORAL NAIL ANTI-ROTATION IN SUPINE "SCISSORS" POSITION AND IN LITHOTOMY POSITION TO TREAT FEMORAL INTERTROCHANTERIC FRACTURES OF OLD PATIENTS].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2016 Feb;30(2):152-5

Objective: To compare the effectiveness of proximal femoral nail anti-rotation (PFNA) between in the supine "scissors" position and in the lithotomy position for treating femoral intertrochanteric fractures of old patients.

Methods: A retrospective study was performed on 58 patients with femoral intertrochanteric fractures treated with PFNA between January 2013 and January 2015. Fracture was treated with PFNA in the lithotomy position in 28 cases (group A) and in the supine "scissors" position in 30 cases (group B). There was no significant difference in gender, age, side, cause of injury, fracture type, and interval from injury to operation between 2 groups (P>0.05). The incision length, operation time, perspective times, intraoperative blood loss, complications, and fracture healing time were recorded; Harris hip score was used to access the effectiveness.

Results: The wound healed by first intention without infection, pressure sores, deep vein thrombosis of lower extremity, and other complications. There was no significant difference in incision length between 2 groups (t=1.313, P=0.212). Group B was significantly better than group A in operation time, perspective times, and intraoperative blood loss (P<0.05). All patients were followed up 10-31 months (mean, 15.3 months). Stretch injury at normal side and perineal discomfort occurred in 1 case and 5 cases of group A respectively, and no nonunion and other complications was observed in the other patients. There was no significant difference in fracture healing time and Harris hip score at last follow-up between 2 groups (P>0.05).

Conclusion: PFNA in the supine "scissors" position has exact effectiveness and advantages of shorter operation time, less intraoperative blood loss, less perspective times, and fewer complications.
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February 2016
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