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1.  Concerted actions of the catechol O-methyltransferase and the cytosolic sulfotransferase SULT1A3 in the metabolism of catecholic drugs 
Biochemical pharmacology  2012;84(9):1186-1195.
Catecholic drugs had been reported to be metabolized through conjugation reactions, particularly methylation and sulfation. Whether and how these two Phase II conjugation reactions may occur in a concerted manner, however, remained unclear. The current study was designed to investigate the methylation and/or sulfation of five catecholic drugs. Analysis of the spent media of HepG2 cells metabolically labeled with [35S]sulfate in the presence of individual catecholic drugs revealed the presence of two [35S]sulfated metabolites for dopamine, epinephrine, isoproterenol, and isoetharine, but only one [35S]sulfated metabolite for apomorphine. Further analyses using tropolone, a catechol O-methyltransferase (COMT) inhibitor, indicated that one of the two [35S]sulfated metabolites of dopamine, epinephrine, isoproterenol, and isoetharine was a doubly conjugated (methylated and sulfated) product, since its level decreased proportionately with increasing concentrations of tropolone added to the labeling media. Moreover, while the inhibition of methylation resulted in a decrease of the total amount of [35S]sulfated metabolites, sulfation appeared to be capable of compensating the suppressed methylation in the metabolism of these four catecholic drugs. A two-stage enzymatic assay showed the sequential methylation and sulfation of dopamine, epinephrine, isoproterenol, and isoetharine mediated by, respectively, the COMT and the cytosolic sulfotransferase SULT1A3. Collectively, the results from the present study implied the concerted actions of the COMT and SULT1A3 in the metabolism of catecholic drugs.
PMCID: PMC3622478  PMID: 22917559
Methylation; Sulfation; COMTs; SULTs; Catecholic drugs
2.  Sulfation of ractopamine and salbutamol by the human cytosolic sulfotransferases 
Journal of Biochemistry  2012;152(3):275-283.
Feed additives such as ractopamine and salbutamol are pharmacologically active compounds, acting primarily as β-adrenergic agonists. This study was designed to investigate whether the sulfation of ractopamine and salbutamol may occur under the metabolic conditions and to identify the human cytosolic sulfotransferases (SULTs) that are capable of sulfating two major feed additive compounds, ractopamine and salbutamol. A metabolic labelling study showed the generation and release of [35S]sulfated ractopamine and salbutamol by HepG2 human hepatoma cells labelled with [35S]sulfate in the presence of these two compounds. A systematic analysis using 11 purified human SULTs revealed SULT1A3 as the major SULT responsible for the sulfation of ractopamine and salbutamol. The pH dependence and kinetic parameters were analyzed. Moreover, the inhibitory effects of ractopamine and salbutamol on SULT1A3-mediated dopamine sulfation were investigated. Cytosol or S9 fractions of human lung, liver, kidney and small intestine were examined to verify the presence of ractopamine-/salbutamol-sulfating activity in vivo. Of the four human organs, the small intestine displayed the highest activity towards both compounds. Collectively, these results imply that the sulfation mediated by SULT1A3 may play an important role in the metabolism and detoxification of ractopamine and salbutamol.
PMCID: PMC3529569  PMID: 22763752
feed additive; ractopamine; salbutamol; sulfation; SULT
3.  Identification and Characterization of Zebrafish SULT1 ST9, SULT3 ST4, and SULT3 ST5 
By searching the GenBank database, we identified sequences encoding three new zebrafish cytosolic sulfotransferases (SULTs). These three new zebrafish SULTs, designated SULT1 ST9, SULT3 ST4, and SULT3 ST5, were cloned, expressed, purified, and characterized. SULT1 ST9 appeared to be mostly involved in the metabolism and detoxification of xenobiotics such as β-naphthol, β-naphthylamine, caffeic acid and gallic acid. SULT3 ST4 showed strong activity toward endogenous compound such as dehydroepiandrosterone (DHEA), pregnenolone, and 17β-estradiol. SULT3 ST5 showed weaker, but significant, activities toward endogenous compounds such as DHEA and corticosterone, as well as xenobiotics including mestranol, β-naphthylamine, β-naphthol, and butylated hydroxyl anisole (BHA). pH-dependency and kinetic constants of these three enzymes were determined with DHEA, β-naphthol, and 17β-estradiol as substrates. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to examine the expression of these three new zebrafish SULTs at different developmental stages during embryogenesis, through larval development, and on to maturity.
PMCID: PMC3521529  PMID: 22360938
Cytosolic sulfotransferase; SULT; 17β-estradiol; dehydroepiandrosterone; molecular cloning; developmental expression; zebrafish
4.  A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs) 
The current study was designed to examine the sulfation of bile acids and bile alcohols by the Zebra danio (Danio rerio) SULTs in comparison with human SULTs. A systematic analysis using the fifteen Zebra danio SULTs revealed that SULT3 ST2 and SULT3 ST3 were the major bile acid/alcohol-sulfating SULTs. Among the eleven human SULTs, only SULT2A1 was found to be capable of sulfating bile acids and bile alcohols. To further investigate the sulfation of bile acids and bile alcohols by the two Zebra danio SULT3 STs and the human SULT2A1, pH-dependence and kinetics of the sulfation of bile acids/alcohols were analyzed. pH-dependence experiments showed that the mechanisms underlying substrate recognition for the sulfation of lithocholic acid (a bile acid) and 5α-petromyzonol (a bile alcohol) differed between the human SULT2A1 and the Zebra danio SULT3 ST2 and ST3. Kinetic analysis indicated that both the two Zebra danio SULT3 STs preferred petromyzonol as substrate compared to bile acids. In contrast, the human SULT2A1 was more catalytically efficient toward lithocholic acid than petromyzonol. Collectively, the results imply that the Zebra danio and human SULTs have evolved to serve for the sulfation of, respectively, bile alcohols and bile acids, matching the cholanoid profile in these two vertebrate species.
PMCID: PMC3515676  PMID: 21839837
Sulfotransferase; Sulfation; Zebra danio; Bile acid
5.  Identification, Characterization, and Ontogenic Study of a Catechol O-methyltransferase from Zebrafish 
To establish the zebrafish as a model for investigating the methylation pathway of drug metabolism, we embarked on the molecular cloning of the zebrafish catechol O-methyltransferase (COMT). By searching the GenBank database, a zebrafish nucleotide sequence encoding a putative COMT was identified. Based on the sequence information, we designed and synthesized oligonucleotides corresponding to its 5’- and 3’-coding regions of this zebrafish COMT. Using the first-strand cDNA reverse-transcribed from the total RNA isolated from a 3-month-old adult female zebrafish as the template, the cDNA encoding the zebrafish COMT was PCR-amplified. The recombinant zebrafish COMT protein was subsequently expressed in and purified from BL21 (DE3) Escherichia coli cells transformed with the pGEX-2TK expression vector harboring the zebrafish COMT cDNA. Upon enzymatic characterization, purified COMT displayed methylating activity toward dopamine, dopa, and catecholestrogens, as well as three representative catechol drugs, methyldopa, dobutamine, and isoproterenol. A reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed developmental stage-dependent expression of the zebrafish COMT during embryonic development and throughout the larval stage onto maturity. These results provide a foundation for investigating the involvement of COMT-mediated methylation in protection against the adverse effects of catechol drugs and other xenobiotic catechols during the developmental process.
PMCID: PMC3515678  PMID: 21371608
Catechol O-methyltransferase; developmental expression; methylation; molecular cloning; zebrafish
6.  A Target-specific Approach for the Identification of Tyrosine-sulfated Hemostatic Proteins 
Analytical biochemistry  2009;390(1):88-90.
A simple methodology for the identification of hemostatic proteins that are subjected to post-translational tyrosine sulfation was developed. The procedure involved sequence analysis of members of the three hemostatic pathways using Sulfinator prediction algorithm, followed by [35S]sulfate-labeling of cultured HepG2 human hepatoma cells, immunoprecipitation of targeted [35S]sulfate-labeled hemostatic proteins, and tyrosine O[35S]sulfate analysis of immunoprecipitated proteins. Three new tyrosine-sulfated hemostatic proteins, protein S, prekallikrein and plasminogen, were identified. Such a target-specific approach will allow for investigation of tyrosine-sulfated proteins of other biochemical/physiological pathways/processes and contribute to a better understating of the functional role of post-translational tyrosine sulfation.
PMCID: PMC2695991  PMID: 19351526
Hemostasis; tyrosine sulfation; post-translational protein modification
7.  Three-Day-Old Human Unfertilized Oocytes after In Vitro Fertilization/Intracytoplasmic Sperm Injection Can Be Activated by Calcium Ionophore A23187 or Strontium Chloride and Develop to Blastocysts 
Cellular Reprogramming  2014;16(4):276-280.
Our objective was to observe the effectiveness of the calcium ionophore A23187 or strontium chloride on the activation and subsequent embryonic development of 3-day-old human unfertilized oocytes after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). A total of 279 3-day-old unfertilized oocytes after IVF or ICSI were randomized to be activated by the calcium ionophore A23187 (n=138) or strontium chloride (n=141). The activated oocytes were cultured in vitro for 3–5 days. Activation rate, pronucleus formation, cleavage rate, and developmental potential of parthenotes during culture were evaluated. A total of 170 unfertilized oocytes were activated; 65 developed to cleavage stage, 19 developed to greater than the eight-cell stage, and five blastocysts were obtained. The activation rate of the calcium ionophore A23187 group was higher than that of the strontium chloride group (75.4% and 46.8%, respectively; p<0.05); there was significant difference between two groups (p<0.05). Among the 44 cleaved oocytes in the calcium ionophore A23187 group, eight developed to the two- to four-cell stage, 17 developed to the five- to eight-cell stage, 15 developed to greater than the eight-cell stage, and four blastocysts were obtained. Among the 21 cleaved oocytes in the strontium chloride group, six developed to the two- to four- cell stage, 10 developed to the five- to eight-cell stage, four developed to greater than the eight-cell stage, and one blastocyst was obtained. Three-day-old unfertilized human oocytes after IVF or ICSI could be activated by the calcium ionophore A23187 or strontium chloride, and a small part of parthenogenetic embryos developed into blastocysts. The treatment with the calcium ionophore A23187 was better than that of strontium chloride in respect to the activation rate of 3-day-old unfertilized human oocytes after IVF or ICSI.
PMCID: PMC4116138  PMID: 24960285
8.  Comparison of Therapeutic Effect of Recombinant Tissue Plasminogen Activator by Treatment Time after Onset of Acute Ischemic Stroke 
Scientific Reports  2015;5:11743.
We aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) administered at different time windows within the first 6 hours after onset of acute ischemic stroke (AIS). A retrospective analysis was performed of data collected from 194 patients who received rt-PA thrombolysis within 4.5 hours after AIS onset and from 29 patients who received rt-PA thrombolysis between 4.5–6 hours after AIS onset. The National Institutes of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P < 0.05) at 24 hours and 7 days after onset. There was no statistical difference in the modified Rankin score or mortality at day 90 after treatment between the two groups (P > 0.05). In conclusion, AIS patients who received rt-PA treatment between 4.5–6 hours after onset were similar in therapeutic efficacy to those who received rt-PA within 4.5 hours after onset. Our results suggest that intravenous thrombolytic therapy for AIS within 4.5–6 hours after onset is effective and safe.
PMCID: PMC4513278  PMID: 26206308
9.  Investigation of Timing to Switch Control Mode in Powered Knee Prostheses during Task Transitions 
PLoS ONE  2015;10(7):e0133965.
Current powered prosthetic legs require switching control modes according to the task the user is performing (e.g. level-ground walking, stair climbing, walking on slopes, etc.). To allow prosthesis users safely and seamlessly transition between tasks, it is critical to determine when to switch the prosthesis control mode during task transitions. Our previous study defined critical timings for different types of task transitions in ambulation; however, it is unknown whether it is the unique timing that allows safe and seamless transitions. The goals of this study were to (1) systematically investigate the effects of mode switch timing on the prosthesis user’s performance in task transitions, and (2) identify appropriate timing to switch the prosthesis control mode so that the users can seamlessly transition between different locomotion tasks. Five able-bodied (AB) and two transfemoral (TF) amputee subjects were tested as they wore a powered knee prosthesis. The prosthesis control mode was switched manually at various times while the subjects performed different types of task transitions. The subjects’ task transition performances were evaluated by their walking balance and success in performing seamless task transitions. The results demonstrated that there existed a time window within which switching the prosthesis control mode neither interrupted the subjects’ task transitions nor disturbed their walking balance. Therefore, the results suggested the control mode switching of a lower limb prosthesis can be triggered within an appropriate time window instead of a specific timing or an individual phase. In addition, a generalized criterion to determine the appropriate mode switch timing was proposed. The outcomes of this study could provide important guidance for future designs of neurally controlled powered knee prostheses that are safe and reliable to use.
PMCID: PMC4509910  PMID: 26197084
10.  Nitrocobinamide, a New Cyanide Antidote That Can Be Administered by Intramuscular Injection 
Journal of medicinal chemistry  2015;58(4):1750-1759.
Currently available cyanide antidotes must be given by intravenous injection over 5–10 min, making them illsuited for treating many people in the field, as could occur in a major fire, an industrial accident, or a terrorist attack. These scenarios call for a drug that can be given quickly, e.g., by intramuscular injection. We have shown that aquohydroxocobinamide is a potent cyanide antidote in animal models of cyanide poisoning, but it is unstable in solution and poorly absorbed after intramuscular injection. Here we show that adding sodium nitrite to cobinamide yields a stable derivative (referred to as nitrocobinamide) that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection. We also show that the efficacy of nitrocobinamide is markedly enhanced by coadministering sodium thiosulfate (reducing the total injected volume), and we calculate that ∼1.4 mL each of nitrocobinamide and sodium thiosulfate should rescue a human from a lethal cyanide exposure.
PMCID: PMC4494098  PMID: 25650735
11.  Reconfiguration of the Brain Functional Network Associated with Visual Task Demands 
PLoS ONE  2015;10(7):e0132518.
Neuroimaging studies have demonstrated that the topological properties of resting-state brain functional networks are modulated through task performances. However, the reconfiguration of functional networks associated with distinct degrees of task demands is not well understood. In the present study, we acquired fMRI data from 18 healthy adult volunteers during resting-state (RS) and two visual tasks (i.e., visual stimulus watching, VSW; and visual stimulus decision, VSD). Subsequently, we constructed the functional brain networks associated with these three conditions and analyzed the changes in the topological properties (e.g., network efficiency, wiring-cost, modularity, and robustness) among them. Although the small-world attributes were preserved qualitatively across the functional networks of the three conditions, changes in the topological properties were also observed. Compared with the resting-state, the functional networks associated with the visual tasks exhibited significantly increased network efficiency and wiring-cost, but decreased modularity and network robustness. The changes in the task-related topological properties were modulated according to the task complexity (i.e., from RS to VSW and VSD). Moreover, at the regional level, we observed that the increased nodal efficiencies in the visual and working memory regions were positively associated with the increase in task complexity. Together, these results suggest that the increased efficiency of the functional brain network and higher wiring-cost were observed to afford the demands of visual tasks. These observations provide further insights into the mechanisms underlying the reconfiguration of the brain network during task performance.
PMCID: PMC4493060  PMID: 26146993
12.  Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome 
Neuropsychopharmacology  2014;39(8):1955-1967.
Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.
PMCID: PMC4059905  PMID: 24553731
13.  Gpr97 Is Dispensable for Inflammation in OVA-Induced Asthmatic Mice 
PLoS ONE  2015;10(7):e0131461.
Asthma is a complex inflammatory disorder involving the activation and invasion of various immune cells. GPR97 is highly expressed in some immunocytes, including mast cells and eosinophils, which play critical roles in asthma development. However, the role of Gpr97 in regulating airway inflammation in asthma has rarely been reported. In this study, we investigated the potential role of Gpr97 in the development of allergic asthma in mice.
Relevant airway asthmatic mouse models were constructed with both wild-type and Gpr97-/- mice sensitized to 250 μg ovalbumin (OVA). The levels of interleukin IL-4, IL-6 and IFN-γ, which are involved in OVA-induced asthma, in the bronchoalveolar lavage fluid (BALF) and the IgE level in the serum were examined by enzyme-linked immunosorbent assay (ELISA). The invasion of mast cells and eosinophils into lung tissues was assessed by immunohistochemical and eosinophil peroxidase activity assays, respectively. Goblet cell hyperplasia and mucus production were morphologically evaluated with periodic acid-Schiff (PAS) staining.
In our study, no obvious alteration in the inflammatory response or airway remodeling was found in the Gpr97-deficient mice with OVA-induced asthma. Neither the secretion of cytokines, including IL-4, IL-6 and IFN-γ, nor inflammatory cell recruitment was altered in the Gpr97-deficient mice. Moreover, Gpr97 deficiency did not affect airway remodeling or mucus production in the asthma mouse model.
Our findings imply that Gpr97 might not be required for the development of airway inflammation in OVA-induced allergic asthma in mice.
PMCID: PMC4489018  PMID: 26132811
14.  Changing risk awareness and personal protection measures for low to high pathogenic avian influenza in live-poultry markets in Taiwan, 2007 to 2012 
BMC Infectious Diseases  2015;15:241.
Outbreaks of low and high pathogenic avian influenza (LPAI, HPAI) H5N2 in chickens have occurred in Taiwan since 2003 and 2012, respectively. Fully understanding the different awareness, attitudes and protective behaviors adopted by workers in live-poultry markets (LPMWs) and local community residents (CRs) to face the challenges of LPAI and HPAI is very important to minimize viral adaptations to human populations.
A structural questionnaire containing information on respondents’ occupation, personal risk awareness, attitudes toward different policies, and preventative measures was administered. The two-stage survey (before and after HPAI H5N2 outbreaks) was conducted from 2007 to 2012, including: (1) 430 LPMWs and 418 CRs at LPMs from different geographical areas of Taiwan after the government announced outbreaks of LPAI H5N2 during 2007–2009, and (2) 73 LPMWs and 152 CRs at two LPMs in central Taiwan after the HPAI H5N2 outbreaks in 2012. The chi-squared test and logistic regression were applied for univariate and multivariate analyses, respectively.
Before HPAI-H5N2 outbreaks, higher educated respondents demonstrated greater risk awareness and concerns regarding AI. However, LPM-workers protected themselves less from AI viruses (AIVs) and had lower acceptance of human or avian influenza vaccines. Most importantly, the participants who opposed (versus agreed with) the policy on banning live-poultry slaughtering at LPMs reported lower awareness of government prevention and control policies [Odds Ratio (OR): 0.76, 95 % Confidence Interval (CI): 0.56–1.01] or practiced preventive measures (OR: 0.42, 95 % CI: 0.25–0.70).
After HPAI-H5N2 outbreaks, the risk awareness about AI in central Taiwan significantly increased [LPAI to HPAI LPMWs: 34.6 to 65.6 %, p < 0.05; CRs: 44.0 to 76.5 %, p < 0.05] and LPMWs’ belief in the effectiveness of vaccination to prevent human or avian influenza virus infection strikingly decreased (92.3 to 68.5 %, p < 0.05).
Risk awareness depends on high or low pathogenicity of AIVs, working in LPMs, levels of education, age, and proximity to the sites of severe AI outbreaks. Regardless of novel LPAI or HPAI virus reassortants that pose public health risks, prompt and clear risk communication focusing on both correct information about AIVs and the most appropriate preventive measures are important for effective prevention of human infection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0987-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4478710  PMID: 26104109
Avian influenza; Cognition; Live-poultry market; Risk communication; Preventive measures; Public health policies; Taiwan
15.  In-Situ Welding Carbon Nanotubes into a Porous Solid with Super-High Compressive Strength and Fatigue Resistance 
Scientific Reports  2015;5:11336.
Carbon nanotube (CNT) and graphene-based sponges and aerogels have an isotropic porous structure and their mechanical strength and stability are relatively lower. Here, we present a junction-welding approach to fabricate porous CNT solids in which all CNTs are coated and welded in situ by an amorphous carbon layer, forming an integral three-dimensional scaffold with fixed joints. The resulting CNT solids are robust, yet still highly porous and compressible, with compressive strengths up to 72 MPa, flexural strengths up to 33 MPa, and fatigue resistance (recovery after 100,000 large-strain compression cycles at high frequency). Significant enhancement of mechanical properties is attributed to the welding-induced interconnection and reinforcement of structural units, and synergistic effects stemming from the core-shell microstructures consisting of a flexible CNT framework and a rigid amorphous carbon shell. Our results provide a simple and effective method to manufacture high-strength porous materials by nanoscale welding.
PMCID: PMC4464184  PMID: 26067176
16.  Glycosylphosphatidylinositol-anchored proteins as chaperones and co-receptors for FERONIA receptor kinase signaling in Arabidopsis 
eLife  null;4:e06587.
The Arabidopsis receptor kinase FERONIA (FER) is a multifunctional regulator for plant growth and reproduction. Here we report that the female gametophyte-expressed glycosylphosphatidylinositol-anchored protein (GPI-AP) LORELEI and the seedling-expressed LRE-like GPI-AP1 (LLG1) bind to the extracellular juxtamembrane region of FER and show that this interaction is pivotal for FER function. LLG1 interacts with FER in the endoplasmic reticulum and on the cell surface, and loss of LLG1 function induces cytoplasmic retention of FER, consistent with transport of FER from the endoplasmic reticulum to the plasma membrane in a complex with LLG1. We further demonstrate that LLG1 is a component of the FER-regulated RHO GTPase signaling complex and that fer and llg1 mutants display indistinguishable growth, developmental and signaling phenotypes, analogous to how lre and fer share similar reproductive defects. Together our results support LLG1/LRE acting as a chaperone and co-receptor for FER and elucidate a mechanism by which GPI-APs enable the signaling capacity of a cell surface receptor.
eLife digest
Plants respond to changes in their environment by altering how they grow and when they reproduce. A protein called FERONIA is found in most types of cells and regulates many of the processes that drive these responses, such as cell growth and communication between male and female cells. FERONIA sits in the membrane that surrounds the cell, where it can detect molecules in the cell wall and from outside the cell, and send signals to locations within the cell. However, it is not clear how FERONIA is able to specifically regulate different processes to produce the right response in a particular cell at a particular time.
A family of proteins called glycosylphosphatidylinositol-anchored proteins (GPI-APs for short) play important roles in plants, animals, and other eukaryotic organisms. Li et al. studied FERONIA and two closely related GPI-APs called LLG1—which is produced in seedlings, and LORELEI, which is only found in female sex cells. The experiments show that plants missing either LLG1 or FERONIA had similar defects in growth and in how they respond to plant hormones. Plants missing LORELEI had similar defects in their ability to reproduce as the plants missing FERONIA. This suggests that FERONIA works with either LLG1 or LORELEI to regulate similar processes in different situations.
Li et al. found that FERONIA binds to LLG1 in a compartment within the cell called the endoplasmic reticulum—where proteins are assembled—before both proteins are moved together to the cell membrane. In the absence of LLG1, FERONIA fails to reach the cell membrane, and a large amount of FERONIA remains trapped in the endoplasmic reticulum. Therefore, LLG1 acts as a ‘chaperone’ that delivers FERONIA to the membrane where it is required to regulate plant growth. Li et al. found that LORELEI also interacts with FERONIA. Both LLG1 and LORELEI bind to the same region of FERONIA, which is on the outer surface of the cell membrane.
These findings show that FERONIA is able to perform different roles in cells by teaming up with different members of the GPI-AP family of proteins. The next challenges will be to find out if, and how, LLG1 and LORELEI affect the ability of FERONIA to respond to signals from the cell wall and outside the cell.
PMCID: PMC4458842  PMID: 26052747
malectin domain-containing receptor kinases; FERONIA and LORELEI/LLG1 as coreceptors; receptor kinase and GPI-AP as functional partners; plant Rho GTPase signaling; RALF; Arabidopsis
17.  Effects of long-term dietary nitrate supplementation in mice 
Redox Biology  2015;5:234-242.
Inorganic nitrate (NO3-) is a precursor of nitric oxide (NO) in the body and a large number of short-term studies with dietary nitrate supplementation in animals and humans show beneficial effects on cardiovascular health, exercise efficiency, host defense and ischemia reperfusion injury. In contrast, there is a long withstanding concern regarding the putative adverse effects of chronic nitrate exposure related to cancer and adverse hormonal effects. To address these concerns we performed in mice, a physiological and biochemical multi-analysis on the effects of long-term dietary nitrate supplementation.
7 week-old C57BL/6 mice were put on a low-nitrate chow and at 20 weeks-old were treated with NaNO3 (1 mmol/L) or NaCl (1 mmol/L, control) in the drinking water. The groups were monitored for weight gain, food and water consumption, blood pressure, glucose metabolism, body composition and oxygen consumption until one group was reduced to eight animals due to death or illness. At that point remaining animals were sacrificed and blood and tissues were analyzed with respect to metabolism, cardiovascular function, inflammation, and oxidative stress.
Animals were supplemented for 17 months before final sacrifice. Body composition, oxygen consumption, blood pressure, glucose tolerance were measured during the experiment, and vascular reactivity and muscle mitochondrial efficiency measured at the end of the experiment with no differences identified between groups. Nitrate supplementation was associated with improved insulin response, decreased plasma IL-10 and a trend towards improved survival.
Long term dietary nitrate in mice, at levels similar to the upper intake range in the western society, is not detrimental.
Graphical abstract
•Long term dietary nitrate supplementation for 17 months in mice.•Nitrate treatment in the upper range in the western society diet, has no adverse health effects.•Chronic nitrate intake in mice improves fasting insulin and insulin response.•Cardiovascular and inflammatory parameters were unchanged after long-term dietary nitrate treatment.
PMCID: PMC4475696  PMID: 26068891
Nitrate; Toxicity; Long-term; Supplementation; Treatment; Survival; ACh, acetylcholine; ADMA, asymmetric dimethylarginine; AU, arbitrary units; AUC, area under the curve; BP, blood pressure; cGMP, cyclic guanidine monophosphate; DeXA, Dual energy X-ray absorptiometry; eNOS, endothelial nitric oxide synthase; HOMA-IR, homeostatic model assessment of insulin resistance; IL-6, interleukin-6; IL-10, interleukin-10; iNOS, inducible nitric oxide synthase; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; MAP, Mean arterial pressure; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; NaCl, sodium chloride; NaNO3, sodium nitrate; NO3-, nitrate; PE, phenylephrine; SDMA, symmetric dimethylarginine; SEM, standard error of measure; SNP, sodium nitroprusside; T3, triiodothyronine; T4, thyroxine
18.  A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Duliang Soft Capsule in Patients with Chronic Daily Headache 
Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo-controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P < 0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH.
PMCID: PMC4460254  PMID: 26101536
19.  The role of perioperative oral nutritional supplementation in elderly patients after hip surgery 
The effect of perioperative oral nutritional supplementation (ONS) on elderly patients after hip surgery remains controversial. This study intended to ascertain whether perioperative ONS is beneficial for the rehabilitation of elderly patients after hip surgery.
Materials and methods
We searched databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials for articles published up to May 2014. Randomized controlled trials of ONS for elderly patients after hip surgery were included.
The combined trials showed that ONS had a positive effect on the serum total protein (P<0.00001) and led to a significantly decreased number of complications (P=0.0005). Furthermore, data from the infection subgroups showed significant decreases in wound infection (P=0.02), respiratory infection (P=0.04), and urinary tract infection (P=0.03). Clinical observation suggests that the intervention may improve the level of serum albumin, although the data did not reach statistical significance (P=0.48). Regarding mortality, there was no significant statistical difference between the intervention group and the control (P=0.93).
Based on the evidence available, this meta-analysis is consistent with the hypothesis that perioperative ONS can help elderly patients recover after hip surgery and reduce complications.
PMCID: PMC4433048  PMID: 26005339
oral nutrition; elderly patient; hip surgery; meta-analysis
20.  Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure 
Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM). Smokers exhibit low circulating levels of total adiponectin (ADPN) and high-molecular-weight (HMW) ADPN multimers. Blood concentrations of HMW ADPN multimers closely correlate with insulin sensitivity for handling glucose. How tobacco smoke exposure lowers blood levels of ADPN, however, has not been investigated. In the current study, we examined the effects of tobacco smoke exposure in vitro and in vivo on the intracellular and extracellular distribution of ADPN and its HMW multimers, as well as potential mechanisms.
We found that exposure of cultured adipocytes to tobacco smoke extract (TSE) suppressed total ADPN secretion, and TSE administration to mice lowered their plasma ADPN concentrations. Surprisingly, TSE caused intracellular accumulation of HMW ADPN in cultured adipocytes and in the adipose tissue of wild-type mice, while preferentially decreasing HMW ADPN in culture medium and in plasma. Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum. In addition, TSE down-regulated DsbA-L, a factor for ADPN secretion.
Tobacco smoke exposure traps HMW ADPN intracellularly, thereby blocking its secretion. Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers.
PMCID: PMC4465313  PMID: 26075006
Adiponectin; Tobacco smoke; Adipocytes
21.  The prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population: a prospective study 
There is limited information on prevalent and incident atrial fibrillation in Chinese. We aimed to investigate the prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population.
In a population—based prospective study in elderly (≥60 years) Chinese, we performed cardiovascular health examinations including a 12-lead electrocardiogram at baseline in 3,922 participants and biennially during follow-up in 2,017 participants. We collected information on vital status during the whole follow-up period.
The baseline prevalence of atrial fibrillation was 2.0 % (n = 34) in 1718 men and 1.6 % (n = 36) in 2204 women. During a median 3.8 years of follow-up, the incidence rate of atrial fibrillation (n = 34) was 4.9 per 1000 person-years (95 % confidence interval [CI], 3.4–6.9). In univariate analysis, both the prevalence and incidence of atrial fibrillation were higher with age advancing (P < 0.0001) and in the presence of coronary heart disease (P ≤ 0.02). Of the 104 prevalent and incident cases of atrial fibrillation, only 1 (1.0 %) received anticoagulant therapy (warfarin). These patients with atrial fibrillation, compared with those with sinus rhythm, had significantly higher risks of all-cause (n = 261, hazard ratio [HR] 1.87, 95 % CI, 1.09–3.20, P = 0.02), cardiovascular (n = 136, HR 3.78, 95 % CI 2.17–6.58, P < 0.0001) and stroke mortality (n = 44, HR 6.31, 95 % CI 2.81–14.19, P = 0.0003).
Atrial fibrillation was relatively frequent in elderly Chinese, poorly managed and associated with higher risks of mortality.
PMCID: PMC4427946  PMID: 25953603
Atrial fibrillation; Epidemiology; Elderly Chinese; Mortality
22.  Does Lower Limb Exercise Worsen Renal Artery Hemodynamics in Patients with Abdominal Aortic Aneurysm? 
PLoS ONE  2015;10(5):e0125121.
Renal artery stenosis (RAS) and renal complications emerge in some patients after endovascular aneurysm repair (EVAR) to treat abdominal aorta aneurysm (AAA). The mechanisms for the causes of these problems are not clear. We hypothesized that for EVAR patients, lower limb exercise could negatively influence the physiology of the renal artery and the renal function, by decreasing the blood flow velocity and changing the hemodynamics in the renal arteries. To evaluate this hypothesis, pre- and post-operative models of the abdominal aorta were reconstructed based on CT images. The hemodynamic environment was numerically simulated under rest and lower limb exercise conditions. The results revealed that in the renal arteries, lower limb exercise decreased the wall shear stress (WSS), increased the oscillatory shear index (OSI) and increased the relative residence time (RRT). EVAR further enhanced these effects. Because these parameters are related to artery stenosis and atherosclerosis, this preliminary study concluded that lower limb exercise may increase the potential risk of inducing renal artery stenosis and renal complications for AAA patients. This finding could help elucidate the mechanism of renal artery stenosis and renal complications after EVAR and warn us to reconsider the management and nursing care of AAA patients.
PMCID: PMC4422666  PMID: 25946196
23.  Minocycline does not affect long-term potentiation in the anterior cingulate cortex of normal adult mice 
Molecular Pain  2015;11:25.
It has been reported that activated microglia plays important roles in chronic pain-related sensory signaling at the spinal cord dorsal horn. Less is known about the possible contribution of microglia to cortical plasticity that has been found to be important for chronic pain. In the present study, we used a 64-channel multi-electrode array recording system to investigate the role of microglia in cortical plasticity of the anterior cingulate cortex (ACC) in normal adult mice. We found that bath application of minocycline, an inhibitor of microglial activation, had no effect on postsynaptic LTP (post-LTP) induced by theta burst stimulation in the ACC. Furthermore, presynaptic LTP (pre-LTP) induced by the combination of low-frequency stimulation with a GluK1-containing kainate receptor agonist was also not affected. The spatial distribution of post-LTP or pre-LTP among the cingulate network is also unaltered by minocycline. Our results suggest that minocycline does not affect cingulate plasticity and neurons are the major player in pain-related cortical plasticity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12990-015-0025-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4464617  PMID: 25933605
Minocycline; Multi-electrode array; Presynaptic long-term potentiation; Postsynaptic long-term potentiation; Anterior cingulate cortex
24.  Influence of Preoperative Peripheral Parenteral Nutrition with Micronutrients after Colorectal Cancer Patients 
BioMed Research International  2015;2015:535431.
Background. The inflammatory reactions are stronger after surgery of malnourished preoperative patients. Many studies have shown vitamin and trace element deficiencies appear to affect the functioning of immune cells. Enteral nutrition is often inadequate for malnourished patients. Therefore, total parenteral nutrition (TPN) is considered an effective method for providing preoperative nutritional support. TPN needs a central vein catheter, and there are more risks associated with TPN. However, peripheral parenteral nutrition (PPN) often does not provide enough energy or nutrients. Purpose. This study investigated the inflammatory response and prognosis for patients receiving a modified form of PPN with added fat emulsion infusion, multiple vitamins (MTV), and trace elements (TE) to assess the feasibility of preoperative nutritional support. Methods. A cross-sectional design was used to compare the influence of PPN with or without adding MTV and TE on malnourished abdominal surgery patients. Results. Both preoperative groups received equal calories and protein, but due to the lack of micronutrients, patients in preoperative Group B exhibited higher inflammation, lower serum albumin levels, and higher anastomotic leak rates and also required prolonged hospital stays. Conclusion. Malnourished patients who receive micronutrient supplementation preoperatively have lower postoperative inflammatory responses and better prognoses. PPN with added fat emulsion, MTV, and TE provides valid and effective preoperative nutritional support.
PMCID: PMC4426776  PMID: 26000296
25.  Cropped, Drosophila transcription factor AP-4, controls tracheal terminal branching and cell growth 
Endothelial or epithelial cellular branching is vital in development and cancer progression; however, the molecular mechanisms of these processes are not clear. In Drosophila, terminal cell at the end of some tracheal tube ramifies numerous fine branches on the internal organs to supply oxygen. To discover more genes involved in terminal branching, we searched for mutants with very few terminal branches using the Kiss enhancer-trap line collection.
In this analysis, we identified cropped (crp), encoding the Drosophila homolog of the transcription activator protein AP-4. Overexpressing the wild-type crp gene or a mutant that lacks the DNA-binding region in either the tracheal tissues or terminal cells led to a loss-of-function phenotype, implying that crp can affect terminal branching. Unexpectedly, the ectopic expression of cropped also led to enlarged organs, and cell-counting experiments on the salivary glands suggest that elevated levels of AP-4 increase cell size and organ size. Like its mammalian counterpart, cropped is controlled by dMyc, as ectopic expression of dMyc in terminal cells increased cellular branching and the Cropped protein levels in vivo.
We find that the branching morphogenesis of terminal cells of the tracheal tubes in Drosophila requires the dMyc-dependent activation of Cropped/AP-4 protein to increase the cell growth of terminal cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12861-015-0069-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4430030  PMID: 25888431
Drosophila; Transcription factor AP-4; Cellular branching; Cell growth; Trachea; Myc

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