Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province

Wuhan, China

Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province

Wuhan, China
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Wang C.-M.,Huazhong University of Science and Technology | Yang Y.-J.,Huazhong University of Science and Technology | Yang Y.-J.,Jiangxi Mental Hospital | Zhang J.-T.,Huazhong University of Science and Technology | And 13 more authors.
Journal of Neurochemistry | Year: 2015

As an endogenous gaseous molecule, hydrogen sulfide (H2S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2S could regulate emotional memory. It was shown that the H2S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2S-associated signaling may hold potential as a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2S) on amygdala-mediated emotional memory was investigated. It was found that H2S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2S-associated signaling may be a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2S) on amygdala-mediated emotional memory was investigated. It was found that H2S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2S-associated signaling may be a new target for the treatment of emotional disorders. © 2014 International Society for Neurochemistry.


Shen J.Z.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | Ma L.N.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | Han Y.,Huazhong University of Science and Technology | Liu J.X.,Huazhong University of Science and Technology | And 8 more authors.
Diabetologia | Year: 2012

Aims/hypothesis Pentamethylquercetin (PMQ) has recently been shown to have glucose-lowering properties. Here, we aimed to characterise the effectiveness and underlying mechanisms of PMQ for ameliorating metabolic disorders in vivo and vitro. Methods We generated a mouse model of obesity by neonatal administration of monosodium glutamate (MSG) and used it to assess the properties of PMQ as a treatment for metabolic disorders. We also investigated the possible underlying mechanisms of PMQ in the prevention of metabolic disorders. Results Compared with normal mice, MSG mice had metabolic disorders, including central obesity, hyperinsulinaemia, insulin resistance, hyperglycaemia, hyperlipidaemia, decreased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated levels of GLUT4 in gastrocnemius muscles. In MSG mice, PMQ treatment (5, 10, 20 mg/kg daily) reduced body weight gain, waist circumference, adipose tissue mass, serum glucose, triacylglycerol and total cholesterol, while improving insulin resistance, activating AMPK and increasing ACC phosphorylation and GLUT4 abundance. In C2C12 myotubes, PMQ (10 μmol/l) increased glucose consumption by ∼65%. PMQ treatment (1-10 μmol/l) also activated AMPK, increased ACC phosphorylation and GLUT4 abundance, and upregulated the expression of some key genes involved in fatty acid oxidation. Conclusions/interpretation These findings suggest that PMQ can ameliorate metabolic disorders at least in part via stimulation of AMPK activity. Keywords AMP-activated protein kinase, Fatty acid oxidation, Glucose transporter type 4, Insulin resistance. © Springer-Verlag 2012.


Li X.-H.,Huazhong University of Science and Technology | Li X.-H.,JiShou University | Xin X.,Huazhong University of Science and Technology | Xin X.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | And 16 more authors.
Journal of Alzheimer's Disease | Year: 2013

Diabetic patients have a signifiantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addition, dendritic spine density and the % cell viability significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflicted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine density, at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addition, PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is associated with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes. © 2013 - IOS Press and the authors. All rights reserved.


Li Y.-K.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | Wang F.,Key Laboratory of Neurological Diseases HUST | And 14 more authors.
Neuropsychopharmacology | Year: 2012

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression. © 2012 American College of Neuropsychopharmacology. All rights reserved.


Wang Y.,Huazhong University of Science and Technology | Guan X.-L.,Huazhong University of Science and Technology | Wu P.-F.,Huazhong University of Science and Technology | Wang C.-M.,Huazhong University of Science and Technology | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2012

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases. © 2012 American Chemical Society.


Wang Y.,Huazhong University of Science and Technology | Chen M.-S.,Huazhong University of Science and Technology | Liu H.-C.,Huazhong University of Science and Technology | Xiao J.-H.,Huazhong University of Science and Technology | And 3 more authors.
Cellular Physiology and Biochemistry | Year: 2014

Background/Aims: Cardiac action potential duration (APD) is regulated by heart rate, leading to the trans-membrane movement of inorganic ions. Whether the alteration of heart rate can affect the expression of transient receptor potential canonical channels (TRPCs), further studies should be made. We investigated the changes of APD at different stimulus frequencies and their influences on the expression of TRPCs in rabbit ventricular myocardium. Methods: Monophasic action potential (MAP) was recorded by contact electrode technique in different programmed stimulus frequencies on rabbit ventricular epicardium in vivo, and the expression of TRPCs was detected using RT-PCR and Western blot. Results: At the frequency range of 4.5-7.5 Hz, APD gradually shortened with the increase of stimulus frequency, showing the property of significant frequency dependence in rabbit ventricular myocardium in vivo. Compared with 4.5 Hz group, TRPC3 mRNA and protein expression increased in 6 Hz and 7.5 Hz groups by way of frequency dependence. Both amiodarone (AM) and neferine (Nef) could prolongate APD and showed characters of frequency independence at the designed frequency. In contrast with 4.5 Hz control group, it was Nef treatment group rather than AM treatment group that could obviously increase the expression of TRPC3 mRNA and protein. Conclusions: At the frequency range of 4.5-7.5 Hz, frequency-dependent shortening of APD was associated with the expression of TRPC3. AM and Nef exhibited frequency-independent lengthening of the APD. Nef may prolong APD via the increasement of TRPC3. © 2014 S. Karger AG, Basel.


Shu Q.,Huazhong University of Science and Technology | Hu Z.-L.,Huazhong University of Science and Technology | Hu Z.-L.,Key Laboratory of Neurological Diseases HUST | Hu Z.-L.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | And 14 more authors.
PLoS ONE | Year: 2014

Orexin-A is an important neuropeptide involved in the regulation of feeding, arousal, energy consuming, and reward seeking in the body. The effects of orexin-A have widely studied in neurons but not in astrocytes. Here, we report that OX1R and OX2R are expressed in cultured rat astrocytes. Orexin-A stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and then induced the migration of astrocytes via its receptor OX1R but not OX2R. Orexin-A-induced ERK1/2 phosphorylation and astrocytes migration are Ca2+-dependent, since they could be inhibited by either chelating the extracellular Ca2+ or blocking the pathway of store-operated calcium entry (SOCE). Furthermore, both non-selective protein kinase C (PKC) inhibitor and PKCα selective inhibitor, but not PKCδ inhibitor, prevented the increase in ERK1/2 phosphorylation and the migration of astrocytes, indicating that the Ca2+-dependent PKCα acts as the downstream of the OX1R activation and mediates the orexin-A-induced increase in ERK1/2 phosphorylation and cell migration. In conclusion, these results suggest that orexin-A can stimulate ERK1/2 phosphorylation and then facilitate the migration of astrocytes via PLC-PKCα signal pathway, providing new knowledge about the functions of the OX1R in astrocytes. © 2014 Shu et al.


Fan H.,Huazhong University of Science and Technology | Wu P.-F.,Huazhong University of Science and Technology | Wu P.-F.,Key Laboratory of Neurological Diseases HUST | Wu P.-F.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | And 16 more authors.
Antioxidants and Redox Signaling | Year: 2015

Aims: Oxidative burst is one of the earliest biochemical events in the inflammatory activation of microglia. Here, we investigated the potential role of methionine sulfoxide reductase A (MsrA), a key antioxidant enzyme, in the control of microglia-mediated neuroinflammation. Results: MsrA was detected in rat microglia and its expression was upregulated on microglial activation. Silencing of MsrA exacerbated lipopolysaccharide (LPS)-induced activation of microglia and the production of inflammatory markers, indicating that MsrA may function as an endogenous protective mechanism for limiting uncontrolled neuroinflammation. Application of exogenous MsrA by transducing Tat-rMsrA fusion protein into microglia attenuated LPS-induced neuroinflammatory events, which was indicated by an increased Iba1 (a specific microglial marker) expression and the secretion of pro-inflammatory cytokines, and this attenuation was accompanied by inhibiting multiple signaling pathways such as p38 and ERK mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-κB). These effects were due to MsrA-mediated reactive oxygen species (ROS) elimination, which may be derived from a catalytic effect of MsrA on the reaction of methionine with ROS. Furthermore, the transduction of Tat-rMsrA fusion protein suppressed the activation of microglia and the expression of pro-inflammatory factors in a rat model of neuroinflammation in vivo. Innovation: This study provides the first direct evidence for the biological significance of MsrA in microglia-mediated neuroinflammation. Conclusion: Our data provide a profound insight into the role of endogenous antioxidative defense systems such as MsrA in the control of microglial function. © Mary Ann Liebert, Inc.


Wang Y.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | Yu J.-P.,CAS Wuhan Institute of Virology | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC50 (-log IC50) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ1-42 self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4′-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca2+ overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease. © 2012 Elsevier Ltd. All rights reserved.


Jiang B.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory of Neurological Diseases HUST | Wang F.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | And 9 more authors.
International Journal of Neuropsychopharmacology | Year: 2015

Background: SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca2+/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulindependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects. Methods: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. Results: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. Conclusion: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway. © 2015 The Author.

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