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1.  Regional effects of endocannabinoid, BDNF and FGF receptor signalling on neuroblast motility and guidance along the rostral migratory stream 
During development and after birth neural stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to populate the olfactory bulb (OB) with neurons. Multiple factors promote neuroblast migration, but the contribution that many of these make to guidance within the intact RMS is not known. In the present study we have characterised in detail how endocannabinoid (eCB), BDNF and FGF receptor (FGFR) signalling regulates motility and guidance, and also determined whether any of these receptors operate in a regionally restricted manner. We used in vivo electroporation in postnatal mice to fluorescently label neuroblasts, and live cell imaging to detail their migratory properties. Cannabinoid receptor antagonists rendered neuroblasts less mobile, and when they did move guidance was lost. Similar results were obtained when eCB synthesis was blocked with diacylglycerol lipase (DAGL) inhibitors, and importantly eCB function is required for directed migration at both ends of the RMS. Likewise, inhibition of BDNF signalling disrupted motility and guidance in a similar manner along the entire RMS. In contrast, altering FGFR signalling inhibits motility and perturbs guidance, but only at the beginning of the stream. Inhibition of FGFR signalling in vivo also reduces the length of the leading process on migratory neuroblasts in a graded manner along the RMS. These results provide evidence for a guidance function for all three of the above receptor systems in the intact RMS, but show that FGFR signalling is unique as it is required in a regionally specific manner.
Highlights
•Live imaging is used to characterise neuroblast migration in the intact RMS.•Endocannabinoids are required for motility and guidance throughout the RMS.•BDNF regulates guidance in a similar manner.•FGFR signalling is also required for guidance, but only at the beginning of the stream.•FGFR regulates neuroblasts morphology in a graded manner along the RMS in vivo.
doi:10.1016/j.mcn.2014.12.001
PMCID: PMC4324876  PMID: 25481343
Neuroblast migration rostral migratory stream; Endocannabinoid; BDNF; FGF
2.  Exploration of Allosteric Agonism Structure-Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254) 
Journal of medicinal chemistry  2013;56(20):7976-7996.
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
doi:10.1021/jm401028t
PMCID: PMC3908770  PMID: 24050755
3.  Splenectomy improves anaemia but does not reduce iron burden in patients with haemoglobin H Constant Spring disease 
Blood Transfusion  2014;12(4):471-478.
Background
Splenectomy is reported to increase the haemoglobin level in patients with haemoglobin H Constant Spring (HbH CS) disease; however, its impact on iron burden and the underlying mechanism remains unclear.
Materials and methods
From March through to May 2013, a total of 50 adults with HbH CS disease (25 cases splenectomised and 25 cases non-splenectomised) were enrolled. The patients’ general conditions, history of blood transfusion and iron chelator treatment were investigated. Levels of haemoglobin, nucleated red blood cell counts, and serum ferritin were measured. The percentage of apoptotic erythroid precursor cells in bone marrow, an index representing ineffective erythropoiesis, was determined in some cases.
Results
There were no significant differences in age, blood transfusion volume, and use of iron chelator drugs between the splenectomised group and the non-splenectomised group. Significantly higher haemoglobin levels, serum ferritin levels and nucleated red blood cell counts as well as a higher percentage of apoptotic erythroid progenitor cells were detected in the splenectomised group. Regression analysis revealed that age and nucleated red blood cell counts were independent risk factors affecting the serum ferritin level.
Discussion
Despite improving the haemoglobin level, splenectomy is associated with greater iron burden in HbH CS disease. A high nucleated red blood cell count is predictive of the risk of severe iron overload.
doi:10.2450/2014.0247-13
PMCID: PMC4212026  PMID: 24960653
haemoglobin H Constant Spring disease; splenectomy; serum ferritin; ineffective erythropoiesis
4.  MicroRNAs expression profile in CCR6+ regulatory T cells 
PeerJ  2014;2:e575.
Backgroud. CCR6+ CD4+ regulatory T cells (CCR6+ Tregs), a distinct Tregs subset, played an important role in various immune diseases. Recent evidence showed that microRNAs (miRNAs) are vital regulators in the function of immune cells. However, the potential role of miRNAs in the function of CCR6+ Tregs remains largely unknown. In this study, we detected the expression profile of miRNAs in CCR6+ Tregs.
Materials and Methods. The expression profile of miRNAs as well as genes in CCR6+ Tregs or CCR6- Tregs from Balb/c mice were detected by microarray. The signaling pathways were analyzed using the Keggs pathway library.
Results. We found that there were 58 miRNAs significantly upregulated and 62 downregulated up to 2 fold in CCR6+ Tregs compared with CCR6- Tregs. Moreover, 1,391 genes were observed with 3 fold change and 20 signaling pathways were enriched using the Keggs pathway library.
Conclusion. The present data showed CCR6+ Tregs expressed specific miRNAs pattern, which provides insight into the role of miRNAs in the biological function of distinct Tregs subsets.
doi:10.7717/peerj.575
PMCID: PMC4179613  PMID: 25279261
CCR6; miRNAs; Regulatory T cell; Microarray
5.  Preventive effect of insect tea against reserpine-induced gastric ulcers in mice 
The aim of the present study was to determine the preventive effect of insect tea against reserpine-induced gastric ulcers in ICR mice. A high (800 mg/kg) dose of insect tea reduced the serum levels of the proinflammatory cytokines interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon (IFN)-γ compared with those in mice treated with a low (400 mg/kg) dose and the control mice. The serum levels of somatostatin (SS) and vasoactive intestinal peptide (VIP) in mice treated with insect tea were higher compared with those in the control mice; however, the serum levels of motilin (MOT) and substance P (SP) were lower in mice treated with insect tea than in the control mice. Gastric ulcer inhibitory rate of the insect tea treatment group of mice were much lower compared to the control mice, and the high concentration treated mice were similar to the ranitidine treated mice. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mice treated with insect tea were higher compared with those in control mice, and similar to those in normal mice and ranitidine-treated mice. The nitric oxide (NO) and maleic dialdehyde (MDA) levels of mice treated with a high concentration of insect tea compared with the normal group were close. Using quantitative polymerase chain reaction (qPCR) assays, the present study revealed that insect tea significantly induced inflammation in the tissues of mice by downregulating the expression of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and upregulating the expression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκB-α). These results suggest that insect tea is as effective at preventing gastric ulcers as the gastric ulcer drug, ranitidine and it can be used as medicine.
doi:10.3892/etm.2014.1859
PMCID: PMC4151677  PMID: 25187847
insect tea; gastric ulcer; cytokine; ICR mice; quantitative polymerase chain reaction
6.  Preventive Effect of Polysaccharide of Larimichthys crocea Swim Bladder on Reserpine Induced Gastric Ulcer in ICR Mice 
This project's aim was to determine the reserpine-induced gastric ulcer preventive effect of polysaccharide of Larimichthys crocea swim bladder (PLCSB) in ICR mice. The anti-gastric ulcer effects of polysaccharide of Larimichthys crocea swim bladder was evaluated in mice model using morphological test, serum levels assay, cytokine levels assay, tissue contents analysis, reverse transcription-polymerase chain reaction (RT-PCR) analysis and western bolt assay. High concentration (50 mg/kg dose) of PLCSB reduced IFN-γ as compared to low concentration (25 mg/kg dose) and control mice. SS and VIP serum levels of PLCSB treated mice were higher than those of control mice, and MOT and SP serum levels were lower than control mice. Gastric ulcer inhibitory index of PLCSB treatment groups mice were much lower than control mice, and the high concentration treated mice were similar to the ranitidine treated mice. The SOD and GSH-Px activities of PLCSB treated mice were higher than control mice, close to normal mice and ranitidine treated mice. PLCSB treated mice also showed the similar contents of NO and MDA to normal group. By RT-PCR and western blot assay, PLCSB significantly induced inflammation in tissues of mice by downregulating NF-κB, iNOS, and COX-2, and upregulating IκB-α. These results suggest that PLCSB showed a good gastric ulcer preventive effect as the gastric ulcer drug of ranitidine. Polysaccharide of Larimichthys crocea swim bladder may be used as a drug material from marine products.
doi:10.4196/kjpp.2014.18.2.183
PMCID: PMC3994307  PMID: 24757382
Cytokine; Gastric ulcer; ICR mice; Larimichthys crocea swim bladder; Polysaccharide
7.  Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent non-covalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease 
Journal of medicinal chemistry  2013;56(2):534-546.
A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a non-covalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multi-component Ugi reaction was utilized to rapidly explore structure activity relationships within S1′, S1, and S2 enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a non-covalent mechanism of action.
doi:10.1021/jm301580n
PMCID: PMC3569073  PMID: 23231439
8.  Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold 
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype.
doi:10.1016/j.bmcl.2012.10.068
PMCID: PMC3539767  PMID: 23142615
metabotropic glutamate receptor 5; mGlu5; positive allosteric modulator (PAM); non-MPEP
9.  The Invasive Wetland Plant Alternanthera philoxeroides Shows a Higher Tolerance to Waterlogging than Its Native Congener Alternanthera sessilis 
PLoS ONE  2013;8(11):e81456.
Plant invasion is one of the major threats to natural ecosystems. Phenotypic plasticity is considered to be important for promoting plant invasiveness. High tolerance of stress can also increase survival of invasive plants in adverse habitats. Limited growth and conservation of carbohydrate are considered to increase tolerance of flooding in plants. However, few studies have examined whether invasive species shows a higher phenotypic plasticity in response to waterlogging or a higher tolerance of waterlogging (lower plasticity) than native species. We conducted a greenhouse experiment to compare the growth and morphological and physiological responses to waterlogging of the invasive, clonal, wetland species Alternanthera philoxeroides with those of its co-occurring, native, congeneric, clonal species Alternanthera sessilis. Plants of A. philoxeroides and A. sessilis were subjected to three treatments (control, 0 and 60 cm waterlogging). Both A. philoxeroides and A. sessilis survived all treatments. Overall growth was lower in A. philoxeroides than in A. sessilis, but waterlogging negatively affected the growth of A. philoxeroides less strongly than that of A. sessilis. Alternanthera philoxeroides thus showed less sensitivity of growth traits (lower plasticity) and higher waterlogging tolerance. Moreover, the photosynthetic capacity of A. philoxeroides was higher than that of A. sessilis during waterlogging. Alternanthera philoxeroides also had higher total non-structural and non-soluble carbohydrate concentrations than A. sessilis at the end of treatments. Our results suggest that higher tolerance to waterlogging and higher photosynthetic capacity may partly explain the invasion success of A. philoxeroides in wetlands.
doi:10.1371/journal.pone.0081456
PMCID: PMC3841148  PMID: 24303048
10.  Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover 
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
doi:10.1016/j.bmcl.2012.08.043
PMCID: PMC3755010  PMID: 22981332
Metabotropic glutamate receptor 5; mGlu5; Positive allosteric modulator (PAM); Non-MPEP
11.  TLR9 signaling repressed tumor suppressor miR-7 expression through up-regulation of HuR in human lung cancer cells 
Background
Our recent evidence showed that Toll like receptor 9 (TLR9) signaling could enhance the growth and metastatic potential of human lung cancer cells through repressing microRNA-7 (miR-7) expression. Human antigen R (HuR) has been involved in stabilizing multiple mRNAs in cellular biology. However, whether HuR also contributed to the altered expression of miR-7 in TLR9 signaling stimulated human lung cancer cells remains to be elucidated.
Methods
The expression of HuR in human lung cancer 95D cells treated with TLR9 agonist CpG Oligonucleotides (ODNs) was detected by Real-time PCR and Western blot assay. To explore the possible role of HuR on miR-7 expression, eukaryotic expression vector encoding HuR was transiently transfected into 95D cells and then the expression of miR-7 was detected by Real-time PCR assay. Moreover, RNA interference, western blot, Real-time PCR, MTT assay, BrdU labeling, invasion assay and scratch assay were employed to examine the disrupt effect of HuR on miR-7 expression in human lung cancer cells treated with CpG ODNs. Finally, inhibitors for PI3K, Akt or Erk respectively, and western blot were performed to explore the possible signaling pathway related to HuR expression in CpG ODNs treated human lung cancer cells.
Results
Our data showed that TLR9 agonist CpG ODNs could induce the expression of HuR in human lung cancer cells. Moreover, overexpression of HuR could reduce the expression of miR-7 in lung cancer cells. Notably, down-regulation of HuR using RNA interference restored miR-7 expression in CpG ODNs treated lung cancer cells, accompanied by enhanced growth and metastatic potential. Finally, CpG ODNs could induce HuR expression through Akt pathway.
Conclusion
Our findings indicated that HuR could act as regulator in regulating TLR9 signaling associated biological effect in human lung cancer cells, which might be helpful for the understanding of the potential role of HuR in tumor biology.
doi:10.1186/1475-2867-13-90
PMCID: PMC3847485  PMID: 24004462
Toll like receptor-9; miR-7; Human antigen R; Human lung cancer cell
12.  Sonographic evaluation of proximal gastric accommodation in patients with functional dyspepsia 
AIM: To assess the value of ultrasonography (US) in evaluation of proximal gastric accommodation disorder in patients with functional dyspepsia (FD).
METHODS: Between April 2011 and March 2012, 45 patients with FD and 27 healthy volunteers were enrolled in this study. Two-dimensional ultrasound (2DUS) and 3-dimensional ultrasound (3DUS) were performed sequentially to measure proximal gastric area (PGA), maximal proximal gastric diameter (MPGD), and proximal gastric volume (PGV). These values were measured separately in the two groups every other 5 min for a duration of 25 min after the beginning of ingestion of a test meal. Air pocket grading was done separately for images of 2DUS and blocks of 3DUS obtained at five scanning time points.
RESULTS: Both PGA and PGV of patients were significantly smaller than healthy controls (P = 0.000 and 0.002, respectively). Comparing the two parameters between the groups at each time point, the differences were also statistically significant (P = 0.000-0.013), except at 10 min for the PGV (P = 0.077). However, no overall difference was found between the groups in the MPGD measurements (P = 0.114), though it was statistically significant at a 20-minute examination point (P = 0.026). A total of 360 sets or blocks of images were obtained for both 2DUS and 3DUS. For the images analyzed by 2DUS, none were excluded because of gastric gas, and 50 (13.9%) and 310 (86.1%) sets were determined as air pockets grades 1 and 2, respectively. For the images analyzed by 3DUS, 23 (6.4%) blocks were excluded from the measurement due to presence of a large fundus air pocket (grade 3); fifty (13.9%) and 287 (79.7%) blocks were also graded as 1 and 2, respectively.
CONCLUSION: Measurement of both PGA and PGV by 2DUS and 3DUS could be useful for assessment of the proximal gastric accommodation.
doi:10.3748/wjg.v19.i29.4774
PMCID: PMC3732851  PMID: 23922476
Functional dyspepsia; Gastric accommodation; Ultrasonography; Diagnosis; 2-dimensional ultrasound; 3-dimensional ultrasound
13.  Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells 
MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1−/− mice showed that CD4+CD25+ regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10–secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPβ, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.
doi:10.4049/jimmunol.1203233
PMCID: PMC3619531  PMID: 23514739
14.  MicroRNA-7–regulated TLR9 signaling–enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/Akt pathway 
Molecular Biology of the Cell  2013;24(1):42-55.
This article reports that TLR9 signaling can reduce intrinsic microRNA-7 (miR-7) expression in human lung cancer cells and that overexpression of miR-7 can significantly inhibit TLR9 signaling–enhanced growth and metastatic potential of lung cancer cells in vitro and in vivo.
Recent evidence shows that microRNAs (miRNAs) contribute to the biological effects of Toll-like receptor (TLR) signaling on various cells. Our previous data showed that TLR9 signaling could enhance the growth and metastatic potential of human lung cancer cells. However, the potential role of miRNAs in the effects of TLR9 signaling on tumor biology remains unknown. In this paper, we first report that TLR9 signaling could reduce intrinsic miR-7 expression in human lung cancer cells. Furthermore, overexpression of miR-7 can significantly inhibit TLR9 signaling–enhanced growth and metastatic potential of lung cancer cells in vitro and in vivo. Notably, we identify phosphoinositide-3-kinase, regulatory subunit 3 (PIK3R3) as a novel target molecule of miR-7 in lung cancer cells by Western blotting and luciferase report assay. Further study shows that miR-7 inhibits the effects of TLR9 signaling on lung cancer cells through regulation of the PIK3R3/Akt pathway. These data suggest that miR-7 could act as a fine-tuner in regulating the biological effects of TLR9 signaling on human lung cancer cells, which might be helpful to the understanding of the potential role of miRNAs in TLR signaling effects on tumor biology.
doi:10.1091/mbc.E12-07-0519
PMCID: PMC3530778  PMID: 23135998
15.  Serum inducible kinase is a positive regulator of cortical dendrite development and is required for BDNF-promoted dendritic arborization 
Cell Research  2011;22(2):387-398.
Serum inducible kinase (SNK), also known as polo-like kinase 2 (PLK2), is a known regulator of mitosis, synaptogenesis and synaptic homeostasis. However, its role in early cortical development is unknown. Herein, we show that snk is expressed in the cortical plate from embryonic day 14, but not in the ventricular/subventricular zones (VZ/SVZ), and SNK protein localizes to the soma and dendrites of cultured immature cortical neurons. Loss of SNK impaired dendritic but not axonal arborization in a dose-dependent manner and overexpression had opposite effects, both in vitro and in vivo. Overexpression of SNK also caused abnormal branching of the leading process of migrating cortical neurons in electroporated cortices. The kinase activity was necessary for these effects. Extracellular signal-regulated kinase (ERK) pathway activity downstream of brain-derived neurotrophic factor (BDNF) stimulation led to increases in SNK protein expression via transcriptional regulation, and this upregulation was necessary for the growth-promoting effect of BDNF on dendritic arborization. Taken together, our results indicate that SNK is essential for dendrite morphogenesis in cortical neurons.
doi:10.1038/cr.2011.100
PMCID: PMC3271584  PMID: 21691298
PLK2; morphogenesis; BDNF; ERK; transcription
16.  MicroRNA-126 regulates the induction and function of CD4+ Foxp3+ regulatory T cells through PI3K/AKT pathway 
Recent evidence showed that limited activation of PI3K/Akt pathway was critical for induction and function sustainment of CD4+Foxp3+ regulatory T cells (Tregs). However, the underlying mechanism remains largely unknown. In this study, we reported that miR-126 was expressed in mouse and human Tregs. Further study showed that silencing of miR-126 using miR-126 antisense oligonucleotides (ASO) could significantly reduce the induction of Tregs in vitro. Furthermore, miR-126 silencing could obviously reduce the expression of Foxp3 on Tregs, which was accompanied by decreased expression of CTLA-4 and GITR, as well as IL-10 and TGF-β, and impair its suppressive function. Mechanistic evidence showed that silencing of miR-126 enhanced the expression of its target p85β and subsequently altered the activation of PI3K/Akt pathway, which was ultimately responsible for reduced induction and suppressive function of Tregs. Finally, we further revealed that miR-126 silencing could impair the suppressive function of Tregs in vivo and endow effectively antitumour effect of CD8+T cells in adoptive cell transfer assay using a murine breast cancer model. Therefore, our study showed that miR-126 could act as fine-tuner in regulation of PI3K-Akt pathway transduction in the induction and sustained suppressive function of Tregs and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating Tregs through targeting specific miRNAs.
doi:10.1111/jcmm.12003
PMCID: PMC3822588  PMID: 23301798
MiR-126; CD4+ regulatory T cell; AKT; Adoptive cell transfer
17.  SUMO-1 Modification on K166 of PolyQ-Expanded aTaxin-3 Strengthens Its Stability and Increases Its Cytotoxicity 
PLoS ONE  2013;8(1):e54214.
Post-translational modification by SUMO was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disease caused by polyQ-expanded ataxin-3. We have previously shown that ataxin-3 was a new target of SUMOylation in vitro and in vivo. Here we identified that the major SUMO-1 binding site was located on lysine 166. SUMOylation did not influence the subcellular localization, ubiquitination or aggregates formation of mutant-type ataxin-3, but partially increased its stability and the cell apoptosis. Our findings revealed the role of ataxin-3 SUMOylation in SCA3/MJD pathogenesis.
doi:10.1371/journal.pone.0054214
PMCID: PMC3561348  PMID: 23382880
18.  Discovery of N-Aryl Piperazines as Selective mGlu5 Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity 
ACS medicinal chemistry letters  2010;1(8):433-438.
This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu5 positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu5 chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a ‘molecular switch’. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu5 receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR5 PAM optimized from an HTS-derived mGluR5 competitive antagonist.
doi:10.1021/ml100181a
PMCID: PMC3539763  PMID: 23308336
mGluR; potentiator; positive allosteric modulator; schizophrenia; hyperlocomotion
19.  C9orf72 mutation is rare in Alzheimer's disease, Parkinson's disease, and essential tremor in China 
GGGGCC repeat expansions in the C9orf72 gene have been identified as a major contributing factor in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the overlapping of clinical phenotypes and pathological characteristics between these two diseases and Alzheimer's disease (AD), Parkinson's disease (PD), and essential tremor (ET), we speculated regarding whether C9orf72 repeat expansions also play a major role in these three diseases. Using the repeat-primed polymerase chain reaction method, we screened for C9orf72 in three groups of patients with PD (n = 911), AD (n = 279), and ET (n = 152) in the Chinese Han population. There were no pathogenic repeats (>30 repeats) detected in either the patients or controls (n = 314), which indicated that the pathogenic expansions of C9orf72 might be rare in these three diseases. However, the analysis of the association between the number of repeats (p = 0.001), short/intermediate genotype (short: <7 repeats; intermediate: ≥7 repeats) (odds ratio 1.37 [1.05, 1.79]), intermediate/intermediate genotype (Odds ratio 2.03 [1.17, 3.54]), and PD risks indicated that intermediate repeat alleles could act as contributors to PD. To the best of our knowledge, this study is the first to reveal the correlation between C9orf72 and Chinese PD, AD, or ET patients. Additionally, the results of this study suggest the novel idea that the intermediate repeat allele in C9orf72 is most likely a risk factor for PD.
doi:10.3389/fncel.2013.00164
PMCID: PMC3782144  PMID: 24068985
C9orf72; Alzheimer's disease; Parkinson's disease; essential tremor; risk factor
20.  Discovery, Synthesis, SAR Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an anti-Parkinsonian Animal Model 
Journal of medicinal chemistry  2011;54(21):7639-7647.
There is an increasing amount of literature data showing the positive effects on preclinical anti-Parkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4).1 However, most of the data generated utilize compounds that have not been optimized for drug-like properties and, as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established anti-Parkinsonian model.
doi:10.1021/jm200956q
PMCID: PMC3226828  PMID: 21966889
metabotropic glutamate receptors; mGlu4; positive allosteric modulators; Parkinson’s disease; haloperidol-induced catalepsy; structure-activity relationship (SAR); oral efficacy; brain penetration
21.  Kirenol production in hairy root culture of Siegesbeckea orientalis and its antimicrobial activity 
Pharmacognosy Magazine  2012;8(30):149-155.
Background:
Despite the excellent anti-inflammatory and anti-rheumatic efficacy associated with kirenol generation, the content of kirenol in Siegesbeckea orientalis is quite low.
Objective:
This study was designed to establish a reliable kirenol production protocol by transformed root cultures of S. orientalis and to investigate the antimicrobial activities of kirenol, hairy root, and S. orientalis.
Materials and Methods:
Transformed root cultures of S. orientalis were established by the transformation of Agrobacterium rhizogenes A4. Transgenic status of the roots was confirmed by polymerase chain reaction (PCR) using rolB specific primers. The biomass and kirenol accumulation of hairy root clones were assessed using four different culture media: MS, MS/2, B5, and white. The antimicrobial activities of kirenol, hairy root, and S. orientalis were evaluated by the disc diffusion method.
Results:
The optimum media for kirenol synthesis was MS. The content of kirenol in transformed hairy roots made up about 80% of that observed in natural leaves of S. orientalis (1.6 mg/g dry weight). All tested samples displayed antimicrobial activity against Gram-positive pathogens including Staphylococcus epidermidis, Staphylococcus aureus, and Acinetobacter baumannii, with MIC ranging from 78 to 625 μg/mL.
Discussion and Conclusion:
The high level of kirenol contents was obtained from hairy roots of S. orientalis. Kirenol was effective against gram-positive bacteria. Interestingly, the extract from hairy roots showed a diverse antimicrobial effect from that of kirenol and S. orientalis.
doi:10.4103/0973-1296.96569
PMCID: PMC3371437  PMID: 22701289
Antimicrobial activity; hairy root culture; kirenol; Siegesbeckia orientalis
22.  Discovery, Synthesis, and Structure Activity Relationship Development of a Series of N-(4-acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu4) with CNS Exposure in Rats 
Journal of medicinal chemistry  2011;54(4):1106-1110.
Herein we report the discovery, synthesis and evaluation of a series of N-(4-acetamido)-phenylpicolinamides as positive allosteric modulators of mGlu4.a Compounds from the series show submicromolar potency at both human and rat mGlu4. In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats.
doi:10.1021/jm101271s
PMCID: PMC3166797  PMID: 21247167
23.  Synthesis and SAR of Novel, Non-MPEP Chemotype mGluR5 NAMs Identified by Functional HTS 
This Letter describes the discovery and SAR of three novel series of mGluR5 noncompetitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology `switch' to provide PAMs with a non-MPEP scaffold.
doi:10.1016/j.bmcl.2009.10.059
PMCID: PMC3177597  PMID: 19875287
24.  Discovery and SAR of Novel mGluR5 Non-Competitive Antagonists Not Based on an MPEP Chemotype 
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology `switch' to provide PAMs with a non-MPEP scaffold.
doi:10.1016/j.bmcl.2009.04.110
PMCID: PMC3177605  PMID: 19443219
25.  Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4 
ACS chemical neuroscience  2010;1(6):411-419.
This Letter describes a detailed SAR analysis of the mGluR4 positive allosteric modulator, PHCCC. We have now developed compounds with improved potency and efficacy; in addition, compounds are presented that show selectivity for mGluR4 versus the other mGluR subtypes.
doi:10.1021/cn9000318
PMCID: PMC2889702  PMID: 20582156
metabotropic glutamate receptor 4; allosteric modulation; positive allosteric modulator; PHCCC; Parkinson's disease; structure-activity relationship; SAR

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