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1.  Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies 
PLoS ONE  2017;12(1):e0169650.
Head injury is reported to be associated with increased risks of dementia and Alzheimer’s disease (AD) in many but not all the epidemiological studies. We conducted a systematic review and meta-analysis to estimate the relative effect of head injury on dementia and AD risks.
Relevant cohort and case-control studies published between Jan 1, 1990, and Mar 31, 2015 were searched in PubMed, Web of Science, Scopus, and ScienceDirect. We used the random-effect model in this meta-analysis to take into account heterogeneity among studies.
Data from 32 studies, representing 2,013,197 individuals, 13,866 dementia events and 8,166 AD events, were included in the analysis. Overall, the pooled relative risk (RR) estimates showed that head injury significantly increased the risks of any dementia (RR = 1.63, 95% CI 1.34–1.99) and AD (RR = 1.51, 95% CI 1.26–1.80), with no evidence of publication bias. However, when considering the status of unconsciousness, head injury with loss of consciousness did not show significant association with dementia (RR = 0.92, 95% CI 0.67–1.27) and AD (RR = 1.49, 95% CI 0.91–2.43). Additionally, this positive association did not reach statistical significance in female participants.
The findings from this meta-analysis indicate that head injury is associated with increased risks of dementia and AD.
PMCID: PMC5221805  PMID: 28068405
2.  GPS-PAIL: prediction of lysine acetyltransferase-specific modification sites from protein sequences 
Scientific Reports  2016;6:39787.
Protein acetylation catalyzed by specific histone acetyltransferases (HATs) is an essential post-translational modification (PTM) and involved in the regulation a broad spectrum of biological processes in eukaryotes. Although several ten thousands of acetylation sites have been experimentally identified, the upstream HATs for most of the sites are unclear. Thus, the identification of HAT-specific acetylation sites is fundamental for understanding the regulatory mechanisms of protein acetylation. In this work, we first collected 702 known HAT-specific acetylation sites of 205 proteins from the literature and public data resources, and a motif-based analysis demonstrated that different types of HATs exhibit similar but considerably distinct sequence preferences for substrate recognition. Using 544 human HAT-specific sites for training, we constructed a highly useful tool of GPS-PAIL for the prediction of HAT-specific sites for up to seven HATs, including CREBBP, EP300, HAT1, KAT2A, KAT2B, KAT5 and KAT8. The prediction accuracy of GPS-PAIL was critically evaluated, with a satisfying performance. Using GPS-PAIL, we also performed a large-scale prediction of potential HATs for known acetylation sites identified from high-throughput experiments in nine eukaryotes. Both online service and local packages were implemented, and GPS-PAIL is freely available at:
PMCID: PMC5177928  PMID: 28004786
3.  PTP1B regulates non-mitochondrial oxygen consumption via RNF213 to promote tumour survival during hypoxia 
Nature cell biology  2016;18(7):803-813.
Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-Tyrosine Phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, though the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2+ xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2+ BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The Moyamoya disease gene product RNF213 , an E3 ligase, is negatively regulated by PTP1B in HER2+ BC cells. RNF213 knockdown reverses the effects of PTP1B-deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2+ BC cells, and partially restores tumourigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2+ BC, and possibly other malignancies, in the hypoxic tumour microenvironment.
PMCID: PMC4936519  PMID: 27323329
4.  APC/CCDC20 and APC/C play pivotal roles in the process of embryonic development in Artemia sinica 
Scientific Reports  2016;6:39047.
Anaphase Promoting Complex or Cyclosome (APC/C) is a representative E3 ubiquitin ligase, triggering the transition of metaphase to anaphase by regulating degradation and ensures the exit from mitosis. Cell division cycle 20 (CDC20) and Cell division cycle 20 related protein 1 (CDH1), as co-activators of APC/C, play significant roles in the spindle assembly checkpoint, guiding ubiquitin-mediated degradation, together with CDC23. During the embryonic development of the brine shrimp, Artemia sinica, CDC20, CDH1 and CDC23 participate in cell cycle regulation, but the specific mechanisms of their activities remain unknown. Herein, the full-length cDNAs of cdc20 and cdc23 from A. sinica were cloned. Real-time PCR analyzed the expression levels of As-cdc20 and As-cdc23. The locations of CDH1, CDC20 and CDC23 showed no tissue or organ specificity. Furthermore, western blotting showed that the levels of As-CDC20, securin, cyclin B, CDK1, CDH1, CDC14B, CDC23 and geminin proteins conformed to their complicated degradation relationships during different embryo stages. Our research revealed that As-CDC20, As-CDH1 and APC mediate the mitotic progression, downstream proteins degradation and cellular differentiation in the process of embryonic development in A. sinica.
PMCID: PMC5171921  PMID: 27991546
5.  A self-assembling nanomedicine of conjugated linoleic acid-paclitaxel conjugate (CLA-PTX) with higher drug loading and carrier-free characteristic 
Scientific Reports  2016;6:36614.
The main objective of this study was to demonstrate the proof-of-principle for the hypothesis that conjugated linoleic acid-paclitaxel conjugate (CLA-PTX), a novel fatty acid modified anti-cancer drug conjugate, could self-assemble forming nanoparticles. The results indicated that a novel self-assembling nanomedicine, CLA-PTX@PEG NPs (about 105 nm), with Cremophor EL (CrEL)-free and organic solvent-free characteristics, was prepared by a simple precipitation method. Being the ratio of CLA-PTX:DSPE-PEG was only 1:0.1 (w/w), the higher drug loading CLA-PTX@PEG NPs (about 90%) possessed carrier-free characteristic. The stability results indicated that CLA-PTX@PEG NPs could be stored for at least 9 months. The safety of CLA-PTX@PEG NPs was demonstrated by the MTD results. The anti-tumor activity and cellular uptake were also confirmed in the in vitro experiments. The lower crystallinity, polarity and solubility of CLA-PTX compared with that of paclitaxel (PTX) might be the possible reason for CLA-PTX self-assembling forming nanoparticles, indicating a relationship between PTX modification and nanoparticles self-assembly. Overall, the data presented here confirm that this drug self-delivery strategy based on self-assembly of a CLA-PTX conjugate may offer a new way to prepare nanomedicine products for cancer therapy involving the relationship between anticancer drug modification and self-assembly into nanoparticles.
PMCID: PMC5095675  PMID: 27812039
6.  Optogenetic Intervention to the Vascular Endothelium 
Vascular pharmacology  2015;74:122-129.
Endothelium lining the interior of cardiovascular system and most visceral organs plays an important role in vascular function. Its dysfunction occurs in some of the most challenging diseases. An important function of the endothelium is to release vasoactive substances that act on the smooth muscle to change vascular tones. Substance secretion from endocrine cells relies on membrane potentials and firing activity, while it is unclear whether the membrane potential regulates substance release from the ECs. Understanding of this requires selective intervention to membrane potentials of the endothelial cells in situ. Here we show a novel intervention to endothelial cells using the optogenetic approach. A strain of transgenic mice was developed with the Cre-loxP recombination system. These transgenic mice expressed channelrhodopsin (ChR) in endothelial cells driven by the vascular endothelial cadherin or cdh5 promoter. Linked in a tandem with YFP, the ChR expression was detected by YFP fluorescence in various endothelium-lining tissues and organs. The YFP fluorescence was observed in the lumen of blood vessels and pericardium, but not in tissues beneath the endothelium lining. Optostimulation of dissociated endothelial cells evoked inward currents and depolarization. In the isolated and perfused heart, surprisingly, optostimulation of endothelial cells produced fast, robust, reproducible and long-lasting vasoconstriction that was not blocked by either ET-1A or TXA2 receptor antagonist. Similar optical vasoconstriction was found in the isolated and perfused kidney. These results indicate that the optogenetics is an effective intervention to vascular endothelium where optostimulation produces vasoconstriction.
Graphical abstract
PMCID: PMC4868400  PMID: 26015375
Endothelium; optogenetics; endothelial cells; channelrhodopsin; transgenic mice; cdh5 promoter
7.  WERAM: a database of writers, erasers and readers of histone acetylation and methylation in eukaryotes 
Nucleic Acids Research  2016;45(Database issue):D264-D270.
In this work, we developed a database WERAM ( for histone acetyltransferases, histone deacetylases, histone methyltransferases, histone demethylases and acetyl- or methyl-binding proteins, which catalyze, remove and recognize histone acetylation and methylation sites as ‘writers’, ‘erasers’ and ‘readers’, and synergistically determine the ‘histone code’. From the scientific literature, we totally collected over 580 experimentally identified histone regulators from eight model organisms, including Homo sapiens, Mus musculus, Rattus norvegicus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Schizosaccharomyces pombe and Saccharomyces cerevisiae. We also collected ∼900 site-specific regulator-histone relations from the eight species. According to the experimental evidence, known histone regulators were classified into distinct families. To computationally detect more proteins in eukaryotes, we constructed hidden Markov model (HMM) profiles for histone regulator families. For families without HMM profiles, we also conducted orthologous searches. Totally, WERAM database contained more than 20 thousand non-redundant histone regulators from 148 eukaryotes. The detailed annotations and classification information of histone regulators were provided, together with site-specific histone substrates if available.
PMCID: PMC5210520  PMID: 27789692
8.  Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome 
Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABAARs, there is a group of GABAARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT.
Wild-type and MECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology.
With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of MECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression.
THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in MECP2-null mice and perhaps in people with RTT as well.
PMCID: PMC5069883  PMID: 27777634
MECP2; Rett syndrome; THIP; Gaboxadol; Behavior; Locus coeruleus
9.  Annexin A2 regulates autophagy in Pseudomonas aeruginosa infection through Akt1-mTOR-ULK1/2 signaling pathway 
Earlier studies reported that a cell membrane protein Annexin A2 (AnxA2) plays multiple roles in the development, invasion and metastasis of cancer. Recent studies have demonstrated that AnxA2 also functions in immunity against infection, but the underlying mechanism remains largely elusive. Using a mouse infection model, we now reveal a crucial role of AnxA2 in host defense against Pseudomonas aeruginosa (Pa), as anxa2−/− mice manifested severe lung injury, systemic dissemination, and increased mortality compared to wild-type (WT) littermates. In addition, anxa2−/− mice exhibited elevated inflammatory cytokines (TNF-α, IL-6, IL-1β and IFN-γ), decreased bacterial clearance by macrophages, and increased superoxide release in the lung. We further identified an unexpected molecular interaction between AnxA2 and Fam13A (Family with sequence similarity 13, member A), which activated Rho GTPase. P. aeruginosa infection induced autophagosome formation by inhibiting Akt1 and mTOR. Our results indicate that AnxA2 regulates autophagy and thereby contributing to host immunity against bacteria through Akt1-mTOR-ULK1/2 signaling pathway.
PMCID: PMC4592832  PMID: 26371245
AnxA2; Pseudomonas aeruginosa; Autophagy; Fam13A; Akt1-mTOR-ULK1/2 signaling pathway
10.  Biotransformation of ferulic acid to vanillin in the packed bed-stirred fermentors 
Scientific Reports  2016;6:34644.
We performed the biotransformation of ferulic acid to vanillin using Bacillus subtilis (B. subtilis) in the stirring packed-bed reactors filled with carbon fiber textiles (CFT). Scanning electron microscope (SEM), HPLC, qRT-PCR and ATP assay indicated that vanillin biotransformation is tightly related to cell growth, cellar activity and the extent of biofilm formation. The biotransformation was affected by hydraulic retention time (HRT), temperature, initial pH, stirring speed and ferulic acid concentration, and the maximum vanillin production was obtained at 20 h, 35 °C, 9.0, 200 rpm, 1.5 g/L, respectively. Repeated batch biotransformation performed under this optimized condition showed that the maximum productivity (0.047 g/L/h) and molar yield (60.43%) achieved in immobilized cell system were 1.84 and 3.61 folds higher than those achieved in free cell system. Therefore, the stirring reactor packed with CFT carrier biofilm formed by B. subtilis represented a valid biocatalytic system for the production of vanillin.
PMCID: PMC5052561  PMID: 27708366
11.  Cardiomyocytes Induce Macrophage Receptor Shedding to Suppress Phagocytosis 
Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology.
To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages.
In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk−/− macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of mycoyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site.
Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.
PMCID: PMC4637185  PMID: 26316303
Acute myocardial infarction; Animal models of human disease; Cardiomyocyte; Phagocytosis
12.  Association between abnormal default mode network activity and suicidality in depressed adolescents 
BMC Psychiatry  2016;16:337.
Suicide is the second leading cause of death among 15- to 29-year-olds in China, and 60 % of suicidal patients have a history of depression. Previous brain imaging studies have shown that depression and suicide may be associated with abnormal activity in default mode network (DMN) regions. However, no study has specifically investigated the relationship between DMN functional activity and suicidal behavior in depressed individuals. Therefore, in the present study, we directly investigated features of DMN brain activity in adolescent patients with histories of depression and attempted suicide.
A total of 35 sex- and age-matched suicidal depressed patients were compared with 18 non-suicidal depressed patients and 47 healthy controls. We explored functional activity changes in DMN regions that could be associated with suicidal behavior by comparing resting-state functional magnetic resonance imaging (rs-fMRI) signals using independent component analysis (ICA). Scores on six clinical scales that measure depression severity (Hamilton Depression Scale (HDRS) and Beck Depression Inventory (BDI)) and suicidal traits (Barratt Impulsiveness Scale (BIS-11), Suicide Attitude Questionnaire (SAQ), Beck Hopelessness Scale (BHS), and Scale for Suicide Ideation (SSI)) were compared in the three groups.
Compared with the healthy controls, all of the evaluated depressed patients showed increased functional connectivity in select DMN regions. The suicidal patients showed increased connectivity in the left cerebellum and decreased connectivity in the right posterior cingulate cortex (PCC), whereas the non-suicidal depressed patients showed increased connectivity in the left superior frontal gyrus, left lingual gyrus and right precuneus and decreased connectivity in the left cerebellum. Compared to the non-suicidal patients, the suicidal patients showed increased connectivity in the left cerebellum and the left lingual gyrus and decreased connectivity in the right precuneus. No differences in the scores of any clinical scales were found between the suicidal and non-suicidal depressed patients.
Collectively, our results highlight the importance of the DMN in the pathophysiology of depression and suggest that suicidal behavior in depressed adolescents may be related to abnormal functional connectivity in the DMN. In particular, abnormal connectivity in the PCC/precuneus and left cerebellum might be a predictor of suicidal behavior in depressed adolescent patients.
PMCID: PMC5041526  PMID: 27688124
Adolescents; Attempted suicide; Default mode network; Depression; rs-fMRI
13.  Broadband metasurface holograms: toward complete phase and amplitude engineering 
Scientific Reports  2016;6:32867.
As a revolutionary three-dimensional imaging technique, holography has attracted wide attention for its ability to photographically record a light field. However, traditional phase-only or amplitude-only modulation holograms have limited image quality and resolution to reappear both amplitude and phase information required of the objects. Recent advances in metasurfaces have shown tremendous opportunities for using a planar design of artificial meta-atoms to shape the wave front of light by optimal control of both its phase and amplitude. Inspired by the concept of designer metasurfaces, we demonstrate a novel amplitude-phase modulation hologram with simultaneous five-level amplitude modulation and eight-level phase modulation. Such a design approach seeks to turn the perceived disadvantages of the traditional phase or amplitude holograms, and thus enable enhanced performance in resolution, homogeneity of amplitude distribution, precision, and signal-to-noise ratio. In particular, the unique holographic approach exhibits broadband characteristics. The method introduced here delivers more degrees of freedom, and allows for encoding highly complex information into designer metasurfaces, thus having the potential to drive next-generation technological breakthroughs in holography.
PMCID: PMC5018728  PMID: 27615519
14.  The Potential Roles of the G1LEA and G3LEA Proteins in Early Embryo Development and in Response to Low Temperature and High Salinity in Artemia sinica 
PLoS ONE  2016;11(9):e0162272.
Late embryogenesis abundant proteins (LEA) are stress resistance-related proteins that play crucial roles in protecting against desiccation, cold and high salinity in a variety of animals and plants. However, the expression pattern, distribution and functions of LEA proteins in the post-diapause period of Artemia sinica, and under high salinity and low temperature stresses, remain unknown. In this study, the complete cDNA sequences of the group 1 LEA (As-g1lea) and group 3 LEA (As-g3lea) genes from A. sinica were cloned. The expression patterns and location of As-G1LEA and As-G1LEA were investigated. The protein abundances of As-G1LEA, As-G3LEA and Trehalase were analyzed during different developmental stages of the embryo and under low temperature and high salinity stresses in A. sinica. The full-length cDNA of As-g1lea was 960 bp, encoding a 182 amino acid protein, and As-g3lea was 2089 bp, encoding a 364 amino acid protein. As-g1lea and As-g3lea showed their highest expressions at 0 h of embryonic development and both showed higher relative expression in embryonic, rather than adult, development stages. The abundances of As-G1LEA, As-G3LEA and trehalose were upregulated under low temperature and downregulated under high salinity stress. These two genes did not show any tissue or organ specific expression. Our results suggested that these LEA proteins might play a pivotal role in stress tolerance in A. sinica
PMCID: PMC5014412  PMID: 27603306
15.  Long-term health effects of persistent exposure to low-dose lr192 gamma-rays 
The aim of the present study was to investigate the effect of persistent low-dose iridium-192 (Ir192) exposure on immunological function, chromosome aberration and the telomerase activity of bone marrow mononuclear cells (BMNCs), in order to increase clinical knowledge of the late effects of persistent low-dose Ir192 gamma-ray exposure. Patients (n=54) accidentally exposed to persistent low-dose Ir192 were included in this 10-year follow-up study. Clinical symptoms, peripheral blood, bone marrow, cellular and humoral immune status, chromosome aberrations and the telomerase activity of BMNCs were analyzed in this study. Exposure to low-dose Ir192 resulted in different degrees of clinical symptoms and significantly lowered complement C3 and C4 levels, CD3+, CD4+ and CD8+ T cell levels, the lymphocyte transformation rate and the percentage of natural killer (NK) cells. It also led to increases in peripheral blood and bone marrow abnormality rates, chromosome aberration rate and BMNC telomerase activity. Exposure to persistent low-dose Ir192 radiation resulted in different degrees of immune dysfunction, and abnormalities of blood cells and bone marrow, which recovered within 1–3 years. Chromosome aberrations were observed to take 5–10 years to recover. However, it would take >10 years for the telomerase activity of BMNCs to be reduced to normal levels. A prolonged follow-up time is required in order to monitor clonal proliferative diseases such as leukemia.
PMCID: PMC5038503  PMID: 27698774
Ir192; telomerase; chromosome aberrations; cellular and humoral immune; follow up
16.  Path Shaping: Shaping 3D Path of Electromagnetic Waves Using Gradient‐Refractive‐Index Metamaterials (Adv. Sci. 8/2016) 
Advanced Science  2016;3(8):n/a.
Cheng‐Wei Qiu, Tie Jun Cui, and co‐workers present an all‐dielectric semispherical lens with functions in shaping 3D wave‐propagation paths in article 1600022. The cover image shows principle of the 3D super‐resolution imaging system, which includes a semispherical magnifying meta‐lens and a planar focusing lens. The semispherical lens magnifies signals of the objects located at the core of lens and the focusing lens gathers the magnified signals and focuses them to generate the image of the objects.
PMCID: PMC5115476
high‐resolution imaging; matched solid immersion lens; metamaterial; path shaping; transformation optics
17.  Photonic Weyl degeneracies in magnetized plasma 
Nature Communications  2016;7:12435.
Weyl particles are elusive relativistic fermionic particles with vanishing mass. While not having been found as an elementary particle, they are found to emerge in solid-state materials where three-dimensional bands develop a topologically protected point-like crossing, a so-called Weyl point. Photonic Weyl points have been recently realised in three-dimensional photonic crystals with complex structures. Here we report the presence of a novel type of plasmonic Weyl points in a naturally existing medium—magnetized plasma, in which Weyl points arise as crossings between purely longitudinal plasma modes and transverse helical propagating modes. These photonic Weyl points are right at the critical transition between a Weyl point with the traditional closed finite equifrequency surfaces and the newly proposed ‘type II' Weyl points with open equifrequency surfaces. Striking observable features of plasmon Weyl points include a half k-plane chirality manifested in electromagnetic reflection. Our study introduces Weyl physics into homogeneous photonic media, which could pave way for realizing new topological photonic devices.
Weyl particles are massless relativistic fermions recently observed in solid-state materials where they are characterized by Weyl points: topologically protected crossings in their band structure. Here, the authors demonstrate a novel type of plasmonic Weyl point in a magnetized plasma.
PMCID: PMC4987518  PMID: 27506514
18.  Rapid generation of functional hepatocyte-like cells from human adipose-derived stem cells 
Liver disease is a major cause of death worldwide. Orthotropic liver transplantation (OLT) represents the only effective treatment for patients with liver failure, but the increasing demand for organs is unfortunately so great that its application is limited. Hepatocyte transplantation is a promising alternative to OLT for the treatment of some liver-based metabolic disorders or acute liver failure. Unfortunately, the lack of donor livers also makes it difficult to obtain enough viable hepatocytes for hepatocyte-based therapies. Currently, a fundamental solution to this key problem is still lacking. Here we show a novel non-transgenic protocol that facilitates the rapid generation of functional induced hepatocytes (iHeps) from human adipose-derived stem cells (hADSCs), providing a source of available cells for autologous hepatocytes to treat liver disease.
We used collagenase digestion to isolate hADSCs. The surface marker was detected by flow cytometry. The multipotential differentiation potency was detected by induction into adipocytes, osteocytes, and chondrocytes. Passage 3–7 hADSCs were induced into iHeps using an induction culture system composed of small molecule compounds and cell factors.
Primary cultured hADSCs presented a fusiform or polygon appearance that became fibroblast-like after passage 3. More than 95 % of the cells expressed the mesenchymal cell markers CD29, CD44, CD166, CD105, and CD90. hADSCs possessed multipotential differentiation towards adipocytes, osteocytes, and chondrocytes. We rapidly induced hADSCs into iHeps within 10 days in vitro; the cellular morphology changed from fusiform to close-connected cubiform, which was similar to hepatocytes. After induction, most of the iHeps co-expressed albumin and alpha-1 antitrypsin; they also expressed mature hepatocyte special genes and achieved the basic functions of hepatocyte. Moreover, iHep transplantation could improve the liver function of acute liver-injured NPG mice and prolong life.
We isolated highly purified hADSCs and rapidly induced them into functional hepatocyte-like cells within 10 days. These results provide a source of available cells for autologous hepatocytes to treat liver disease.
PMCID: PMC4974756  PMID: 27495937
Human adipose derived stem cells; Hepatogenic differentiation; Acute fulminant liver failure; Liver regeneration
19.  Optogenetic approach for functional assays of the cardiovascular system by light activation of the vascular smooth muscle 
Vascular pharmacology  2015;71:192-200.
Cardiovascular diseases are the major challenge to modern medicine. Intervention to cardiovascular cells is crucial for treatment of the diseases. Here we report a novel intervention to vascular smooth muscle (VSM) cells by optogenetics. Channelrhodopsin in a tandem with YFP was selectively expressed in smooth muscle of transgenic mice in which YFP fluorescence was found in arterial walls of various tissues. In dissociated VSM cells from the mice blue light evoked inward currents, leading to depolarization and contraction. In isolated mesenteric arterial rings, optostimulation produced vasoconstriction that was reproducible, sustained, light intensity-dependent and comparable to popular vasoconstrictors. Blue light raised robustly coronary resistance without significant effects on heart rate and pulse pressure. Optostimulation produced renal vasoconstriction as well. The optical vasoconstriction had temporal resolutions less than 40s in these organs. These results indicate that optical vasoconstriction can be effectively produced in various organs with channelrhodopsin expression in VSM cells.
Graphical Abstract
PMCID: PMC4854280  PMID: 25869510
vascular smooth muscle cells; cardiovascular rhodopsin; transgenic mice; optogenetics; Channelrhodopsin
20.  The anti-tumor efficacy of 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX): a novel paclitaxel bioreductive prodrug 
Oncotarget  2016;7(30):48467-48480.
Hypoxia is an important microenvironmental pressure present in the majority of solid tumors and, so, tumor hypoxia might be considered an attractive target for tumor therapy. One strategy for targeting hypoxia is to develop bioreductive prodrugs. In the present research, we synthesized a bioreductive paclitaxel prodrug, 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX). The stability of NPPA-PTX in PBS and rat plasma was investigated. The anti-tumor activity of NPPA-PTX was also evaluated in vitro and in vivo. The results of our stability study indicated that NPPA-PTX was stable in PBS and rat plasma as well as in the blood circulation. The in vitro and in vivo anti-tumor activity of NPPA-PTX was confirmed in both KB cells and MDA-MB-231 cells. Our results also indicated that NPPA-PTX could completely convert to active PTX in tumor tissues and produced the anti-tumor activity in both KB and MDA-MB-231 tumor-bearing nude mice. We suggest that the dissociated PTX which converted from NPPA-PTX in tumor tissues played a key role in producing anti-tumor activity. Considering all our results, we suggest that NPPA-PTX is a novel bioreductive PTX prodrug which could undergo further evaluation.
PMCID: PMC5217032  PMID: 27366947
paclitaxel; 3-(2-Nitrophenyl) propionic acid; bioreductive prodrug; tumor hypoxia; anti-tumor efficacy
21.  Multi-targeting NGR-modified liposomes recognizing glioma tumor cells and vasculogenic mimicry for improving anti-glioma therapy 
Oncotarget  2016;7(28):43616-43628.
Like the anti-angiogenic strategy, anti-vascular mimicry is considered as a novel targeting strategy for glioma. In the present study, we used NGR as a targeting ligand and prepared NGR-modified liposomes containing combretastatin A4 (NGR-SSL-CA4) in order to evaluate their potential targeting of glioma tumor cells and vasculogenic mimicry (VM) formed by glioma cells as well as their anti-VM activity in mice with glioma tumor cells. NGR-SSL-CA4 was prepared by a thin-film hydration method. The in vitro targeting of U87-MG (human glioma tumor cells) by NGR-modified liposomes was evaluated. The in vivo targeting activity of NGR-modified liposomes was tested in U87-MG orthotopic tumor-bearing nude mice. The anti-VM activity of NGR-SSL-CA4 was also investigated in vitro and in vivo. The targeting activity of the NGR-modified liposomes was demonstrated by in vitro flow cytometry and in vivo biodistribution. The in vitro anti-VM activity of NGR-SSL-CA4 was indicated in a series of cell migration and VM channel experiments. NGR-SSL-CA4 produced very marked anti-tumor and anti-VM activity in U87-MG orthotopic tumor-bearing mice in vivo. Overall, the NGR-SSL-CA4 has great potential in the multi-targeting therapy of glioma involving U87-MG cells, and the VM formed by U87-MG cells as well as endothelial cells producing anti-U87-MG cells, and anti-VM formed by U87-MG cells as well as anti-endothelial cell activity.
PMCID: PMC5190048  PMID: 27283987
NGR; combretastatin A4; vascular mimicry; glioma; anti-tumor activity
22.  SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin 
Nature Communications  2016;7:11996.
SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer.
Ceruloplasmin has an important role in the stabilization and nuclear transport of HIF-1α, thus regulating VEGF expression. Here the authors show that the transcription factor SARI reduces colorectal cancer growth and angiogenesis in vivo by inducing the degradation of ceruloplasmin, thereby inhibiting the HIFα/VEGF axis.
PMCID: PMC4931276  PMID: 27353863
23.  High Expression of RIOK2 and NOB1 Predict Human Non-small Cell Lung Cancer Outcomes 
Scientific Reports  2016;6:28666.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. However, there is a shortage of suitable diagnostic markers for early stages of NSCLC, and therapeutic targets are limited. Right open reading frame (Rio) kinase 2 (RIOK2) and Nin one binding (NOB1) protein are important accessory factors in ribosome assembly and are highly expressed in malignant tumours; moreover, they interact with each other. However, the RIOK2 expression profile and its clinical significance as well as NOB1’s mechanism in NSCLC remain unknown. In this study, NSCLC cell lines and 15 NSCLC tumour tissues (paired with adjacent normal lung tissues) were collected for a real-time quantitative PCR (RT-qPCR) analysis. In addition, 153 NSCLC cases and 27 normal lung tissues were used in an immunohistochemical analysis to evaluate the RIOK2 and NOB1 expression profiles, their clinicopathological factors in NSCLC and their correlations with prognoses. RIOK2 and NOB1 were highly expressed in NSCLC cells and tissues, and their expression profiles were significantly associated with the Tumour Node Metastasis (TNM) clinical stage, lymph node metastasis, and differentiation. RIOK2 expression was correlated with NOB1. The results suggested that simultaneously determining the expression of RIOK2 and NOB1 will improve the diagnostic rate in early stages of NSCLC. Moreover, RIOK2 and NOB1 might be potential targets for NSCLC therapy.
PMCID: PMC4921844  PMID: 27346559
24.  Characterization of Rett Syndrome-like phenotypes in Mecp2-knockout rats 
Rett Syndrome (RTT) is a neurodevelopmental disease caused by the disruption of the MECP2 gene. Several mouse models of RTT have been developed with Mecp2 disruptions. Although the mouse models are widely used in RTT research, results obtained need to be validated in other species. Therefore, we performed these studies to characterize phenotypes of a novel Mecp2−/Y rat model and compared them with the Mecp2tm1.1Bird mouse model of RTT.
RTT-like phenotypes were systematically studied and compared between Mecp2−/Y rats and Mecp2−/Y mice. In-cage conditions of the rats were monitored. Grip strength and spontaneous locomotion were used to evaluate the motor function. Three-chamber test was performed to show autism-type behaviors. Breathing activity was recorded with the plethysmograph. Individual neurons in the locus coeruleus (LC) were studied in the whole-cell current clamp. The lifespan of the rats was determined with their survival time.
Mecp2−/Y rats displayed growth retardation, malocclusion, and lack of movements, while hindlimb clasping was not seen. They had weaker forelimb grip strength and a lower rate of locomotion than the WT littermates. Defects in social interaction with other rats were obvious. Breathing frequency variation and apnea in the null rats were significantly higher than in the WT. LC neurons in the null rats showed excessive firing activity. A half of the null rats died in 2 months. Most of the RTT-like symptoms were comparable to those seen in Mecp2−/Y mice, while some appeared more or less severe. The findings that most RTT-like symptoms exist in the rat model with moderate variations and differences from the mouse models support the usefulness of both Mecp2−/Y rodent models.
The novel Mecp2−/Y rat model recapitulated numerous RTT-like symptoms as Mecp2−/Y mouse models did, which makes it a valuable alternative model in the RTT studies when the body size matters.
PMCID: PMC4910223  PMID: 27313794
Mecp2-null rat; Rett syndrome; Behaviors; Breathing; Locus coeruleus
25.  Spin and wavelength multiplexed nonlinear metasurface holography 
Nature Communications  2016;7:11930.
Metasurfaces, as the ultrathin version of metamaterials, have caught growing attention due to their superior capability in controlling the phase, amplitude and polarization states of light. Among various types of metasurfaces, geometric metasurface that encodes a geometric or Pancharatnam–Berry phase into the orientation angle of the constituent meta-atoms has shown great potential in controlling light in both linear and nonlinear optical regimes. The robust and dispersionless nature of the geometric phase simplifies the wave manipulation tremendously. Benefitting from the continuous phase control, metasurface holography has exhibited advantages over conventional depth controlled holography with discretized phase levels. Here we report on spin and wavelength multiplexed nonlinear metasurface holography, which allows construction of multiple target holographic images carried independently by the fundamental and harmonic generation waves of different spins. The nonlinear holograms provide independent, nondispersive and crosstalk-free post-selective channels for holographic multiplexing and multidimensional optical data storages, anti-counterfeiting, and optical encryption.
Metasurfaces offer an approach for computer generated holograms with good efficiency and ease of fabrication. Here, Ye et al. report on spin and wavelength multiplexed nonlinear metasurface holography, showing construction of holographic images using fundamental and harmonic generation waves of different spins.
PMCID: PMC4912630  PMID: 27306147

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