Luo L

References (30)

Title : A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease - Shan_2024_ACS.Nano__
Author(s) : Shan X , Lu Y , Luo Z , Zhao X , Pang M , Yin H , Guo X , Zhou H , Zhang J , Huang J , Shi Y , Lou J , Luo L , You J
Ref : ACS Nano , : , 2024
Abstract : Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Abeta accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.
ESTHER : Shan_2024_ACS.Nano__
PubMedSearch : Shan_2024_ACS.Nano__
PubMedID: 38517764

Title : ABHD6 drives endocytosis of AMPA receptors to regulate synaptic plasticity and learning flexibility - Wei_2023_Prog.Neurobiol__102559
Author(s) : Wei M , Yang L , Su F , Liu Y , Zhao X , Luo L , Sun X , Liu S , Dong Z , Zhang Y , Shi YS , Liang J , Zhang C
Ref : Prog Neurobiol , :102559 , 2023
Abstract : Trafficking of alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. alpha/beta-Hydrolase domain-containing 6 (ABHD6), an endocannabinoid hydrolase, was an AMPAR auxiliary subunit found to negatively regulate the surface delivery of AMPARs. While ABHD6 was found to prevent AMPAR tetramerization in endoplasmic reticulum, ABHD6 was also reported to localize at postsynaptic site. Yet, the role of ABHD6 interacting with AMPAR at postsynaptic site, and the physiological significance of ABHD6 regulating AMPAR trafficking remains elusive. Here, we generated the ABHD6 knockout (ABHD6(KO)) mice and found that deletion of ABHD6 selectively enhanced AMPAR-mediated basal synaptic responses and the surface expression of postsynaptic AMPARs. Furthermore, we found that loss of ABHD6 impaired hippocampal long-term depression (LTD) and synaptic downscaling in hippocampal synapses. AMPAR internalization assays revealed that ABHD6 was essential for neuronal activity-dependent endocytosis of surface AMPARs, which is independent of ABHD6's hydrolase activity. The defects of AMPAR endocytosis and LTD are expressed as deficits in learning flexibility in ABHD6(KO) mice. Collectively, we demonstrated that ABHD6 is an endocytic accessory protein promoting AMPAR endocytosis, thereby contributes to the formation of LTD, synaptic downscaling and reversal learning.
ESTHER : Wei_2023_Prog.Neurobiol__102559
PubMedSearch : Wei_2023_Prog.Neurobiol__102559
PubMedID: 38159878
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6

Title : Discovery of 1,2,4-Oxadiazole Derivatives Containing Haloalkyl as Potential Acetylcholine Receptor Nematicides - Luo_2023_Int.J.Mol.Sci_24_
Author(s) : Luo L , Ou Y , Zhang Q , Gan X
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Plant-parasitic nematodes pose a serious threat to crops and cause substantial financial losses due to control difficulties. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a novel broad-spectrum nematicide developed by the Monsanto Company, which shows good prevention effects on many kinds of nematodes. To discover compounds with high nematocidal activities, 48 derivatives of 1,2,4-oxadiazole were obtained by introducing haloalkyl at the 5-position of tioxazafen, and their nematocidal activities were systematically evaluated. The bioassays revealed that most of 1,2,4-oxadiazole derivatives showed remarkable nematocidal activities against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus dipsaci. Notably, compound A1 showed excellent nematocidal activity against B. xylophilus with LC(50) values of 2.4 microg/mL, which was superior to that of avermectin (335.5 microg/mL), tioxazafen (>300 microg/mL), and fosthiazate (436.9 microg/mL). The transcriptome and enzyme activity results indicate that the nematocidal activity of compound A1 was mainly related to the compound which affected the acetylcholine receptor of B. xylophilus.
ESTHER : Luo_2023_Int.J.Mol.Sci_24_
PubMedSearch : Luo_2023_Int.J.Mol.Sci_24_
PubMedID: 36982843

Title : Is strigolactone signaling a key player in regulating tiller formation in response to nitrogen? -
Author(s) : Luo L
Ref : Front Plant Sci , 13 :1081740 , 2022
PubMedID: 36589130

Title : Enantioselective neurotoxicity and oxidative stress effects of paclobutrazol in zebrafish (Danio rerio) - Guo_2022_Pestic.Biochem.Physiol_185_105136
Author(s) : Guo D , Luo L , Kong Y , Kuang Z , Wen S , Zhao M , Zhang W , Fan J
Ref : Pestic Biochem Physiol , 185 :105136 , 2022
Abstract : Paclobutrazol is a widely used chiral plant growth regulator and its enantioselective toxicity in aquatic organisms is less explored till now. Herein, the enantioselective neurotoxicity of paclobutrazol mediated by oxidative stress in zebrafish were investigated. The oxidative stress parameters and neurotoxic biomarkers changed significantly in each exposure group, and paclobutrazol showed enantioselective toxicity in zebrafish. Firstly, (2R, 3R)-paclobutrazol exhibited a stronger oxidative stress in zebrafish than (2S, 3S)-enantiomer (P < 0.05). Then, activities of acetylcholinesterase, calcineurin, and total nitric oxide synthase in (2R, 3R)-paclobutrazol treatments were 0.61-0.89, 1.24-1.53, and 1.21-1.35-fold stronger (P < 0.05) than those in (2S, 3S)-enantiomer treatments, respectively. Next, the content variations of four neurotransmitters in zebrafish exposed to (2R, 3R)-paclobutrazol were significantly larger than those in (2S, 3S)-enantiomer treatments (P < 0.05). Moreover, (2R, 3R)-paclobutrazol had stronger binding with the receptors than (2S, 3S)-enantiomer through molecular docking. The integrated biomarker response values further demonstrated that (2R, 3R)-paclobutrazol showed stronger toxicity to zebrafish than (2S, 3S)-enantiomer. Furthermore, the neurotoxicity of paclobutrazol can be interpreted as the mediating effect of oxidative stress in zebrafish through correlation analysis, and an adverse outcome pathway for the nervous system in zebrafish induced by paclobutrazol was proposed. This work will greatly extend our understanding on the enantioselective toxic effects of paclobutrazol in aquatic organisms.
ESTHER : Guo_2022_Pestic.Biochem.Physiol_185_105136
PubMedSearch : Guo_2022_Pestic.Biochem.Physiol_185_105136
PubMedID: 35772839

Title : Enantioselective acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole in zebrafish (Danio rerio) - Guo_2022_Environ.Sci.Pollut.Res.Int__
Author(s) : Guo D , He R , Luo L , Zhang W , Fan J
Ref : Environ Sci Pollut Res Int , : , 2022
Abstract : Uniconazole is a widely used plant growth retardant in the agricultural field. However, toxicological effects of uniconazole in aquatic ecosystem at chiral level are still unclear. Herein, acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole enantiomers were investigated through using zebrafish as a model. (R)-Uniconazole possessed 1.16-fold greater acute toxicity to zebrafish than (S)-enantiomer. Then, integrated biomarker response values of oxidative stress parameters in zebrafish exposed to (R)-uniconazole were about 1.27~1.53 times greater than those treated by (S)-uniconazole, revealing that (R)-uniconazole could result in more significant adverse effects than (S)-uniconazole. Subsequently, the results of acetylcholinesterase activity of experimental fish demonstrated a state of inhibition-activation-inhibition after 14-day exposure to uniconazole, and a significant enantioselective neurotoxicity of uniconazole was observed in zebrafish after exposure for 4 and 7 days (p < 0.05). Moreover, thyroxine and triiodothyronine contents in (R)-uniconazole-exposed zebrafish were 0.89-fold (p=0.007) and 0.80-fold (p=0.007) than those in (S)-enantiomer-treated group, respectively. Furthermore, molecular docking results between uniconazole enantiomers and thyroid hormone receptors revealed that (R)-uniconazole was more tightly bound than (S)-uniconazole to the receptors. Briefly, our findings provide favorable information for ecological risk assessments of chiral agrochemicals in the environment and health of aquatic organisms.
ESTHER : Guo_2022_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Guo_2022_Environ.Sci.Pollut.Res.Int__
PubMedID: 35119633

Title : Use of data-independent acquisition mass spectrometry for comparative proteomics analyses of sera from pregnant women with intrahepatic cholestasis of pregnancy - Zou_2021_J.Proteomics__104124
Author(s) : Zou S , Dong R , Wang J , Liang B , Zhu T , Zhao S , Zhang Y , Wang T , Zou P , Li N , Wang Y , Chen M , Zhou C , Zhang T , Luo L
Ref : J Proteomics , :104124 , 2021
Abstract : We used data-independent acquisition (DIA) proteomics technology followed by ELISAs and automated biochemical analyses to identify and validate protein expression levels in Intrahepatic Cholestasis of Pregnancy (ICP) and healthy pregnant controls. We employed bioinformatics to identify metabolic processes associated with differentially expressed proteins.The expression levels of two proteins (S100-A9 and the L-lactate dehydrogenase A chain) were significantly higher in ICP patients than in controls; the areas under the receiver operating characteristic (ROC) curves (AUCs) were 0.774 and 0.828, respectively. The expression levels of two other proteins (apolipoprotein A-I and cholinesterase) were significantly lower in patients, with values of 0.900 and 0.842, respectively. Multiple logistic regression showed that a combination of the levels of the four proteins optimized the AUC (0.962), thus more reliably diagnosing ICP. The levels of all four proteins were positively associated with that of total bile acids. Bioinformatics analyses indicated that the four proteins principally affected neutrophil activation involved in the immune response, cell adhesion, lipoprotein metabolism, and the PPAR signaling pathway. SIGNIFICANCE: This preliminary work improves our understanding of changes in serum levels of protein in pregnant women with ICP. The four proteins may serve as novel noninvasive biomarkers for ICP.
ESTHER : Zou_2021_J.Proteomics__104124
PubMedSearch : Zou_2021_J.Proteomics__104124
PubMedID: 33545297

Title : Metabolism and Interspecies Variation of IMMH-010, a Programmed Cell Death Ligand 1 Inhibitor Prodrug - Wang_2021_Pharmaceutics_13_
Author(s) : Wang Y , Liu X , Zou X , Wang S , Luo L , Liu Y , Dong K , Yao X , Li Y , Chen X , Sheng L
Ref : Pharmaceutics , 13 : , 2021
Abstract : IMMH-010 is an ester prodrug of YPD-29B, a potent programmed cell death ligand 1 (PD-L1) inhibitor. The metabolism of IMMH-010 was investigated and compared in various species. Four metabolites of IMMH-010 were identified, and the major metabolite was the parent compound, YPD-29B, which was mainly catalyzed by carboxylesterase 1 (CES1). We observed IMMH-010 metabolism in the plasma of various species. IMMH-010 was rapidly metabolized to YPD-29B in rat and mouse plasma, whereas it remained stable in human and monkey plasma. In the liver S9 fractions of human, monkey, dog, and rat, IMMH-010 was quickly transformed to YPD-29B with no obvious differences among species. In addition, the transformation ratio of IMMH-010 to YPD-29B was low in rat and human intestines, which indicated that the intestine was not an important site for IMMH-010 hydrolysis. Moreover, we demonstrated the remarkable antitumor efficacy of IMMH-010 in B16F10 melanoma and MC38 colon carcinoma xenograft mouse models. We also compared the pharmacokinetic profiles of IMMH-010 in rodents and primates. After oral administration of IMMH-010, the general exposure of active metabolite YPD-29B was slightly lower in primates than in rodents, suggesting that data should be extrapolated cautiously from rodents to humans.
ESTHER : Wang_2021_Pharmaceutics_13_
PubMedSearch : Wang_2021_Pharmaceutics_13_
PubMedID: 33919384

Title : Bioactive Polyketide and Diketopiperazine Derivatives from the Mangrove-Sediment-Derived Fungus Aspergillus sp. SCSIO41407 - Cai_2021_Molecules_26_
Author(s) : Cai J , Chen C , Tan Y , Chen W , Luo X , Luo L , Yang B , Liu Y , Zhou X
Ref : Molecules , 26 : , 2021
Abstract : Ten polyketide derivatives (1-10), including a new natural product named (E)-2,4-dihydroxy-3-methyl-6-(2-oxopent-3-en-1-yl) benzaldehyde (1), and five known diketopiperazines (11-15), were isolated from the mangrove-sediment-derived fungus Aspergillus sp. SCSIO41407. The structures of 1-15 were determined via NMR and MS spectroscopic analysis. In a variety of bioactivity screening, 3 showed weak cytotoxicity against the A549 cell line, and 2 exhibited weak antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 3, 5, and 6 showed inhibition against acetylcholinesterase (AChE) with IC(50) values of 23.9, 39.9, and 18.6 microM. Compounds 11, 12, and 14 exhibited obvious inhibitory activities of lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-kappaB) with IC(50) values of 19.2, 20.9, and 8.7 microM, and they also suppressed RANKL-induced osteoclast differentiation in bone marrow macrophages cells (BMMCs), with the concentration of 5 microM. In silico molecular docking with AChE and NF-kappaB p65 protein were also performed to understand the inhibitory activities, and 1, 11-14 showed obvious protein/ligand-binding effects to the NF-kappaB p65 protein.
ESTHER : Cai_2021_Molecules_26_
PubMedSearch : Cai_2021_Molecules_26_
PubMedID: 34443439

Title : Inhibition of soluble epoxide hydrolase alleviates insulin resistance and hypertension via downregulation of SGLT2 in the mouse kidney - Luo_2021_J.Biol.Chem__100667
Author(s) : Luo J , Hu S , Fu M , Luo L , Li Y , Li W , Cai Y , Dong R , Yang Y , Tu L , Xu X
Ref : Journal of Biological Chemistry , :100667 , 2021
Abstract : The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension, and the underlying mechanisms of this relationship, are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF-HS) diet. The sEH inhibitor trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was used to treat mice (1 mg/kg/d) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) were markedly upregulated in the kidneys of mice fed a HF-HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2, and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knock-down or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the IKKalpha/beta/NF-kappaB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by a HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression due to inactivation of the IKKalpha/beta/NF-kappaB-induced inflammatory response.
ESTHER : Luo_2021_J.Biol.Chem__100667
PubMedSearch : Luo_2021_J.Biol.Chem__100667
PubMedID: 33864813

Title : Toxic effects of subacute exposure to acrylamide on motor endplates of the gastrocnemius in rats - Yanxian_2021_Toxicology__152934
Author(s) : Yanxian B , Gu Z , Zhang T , Luo Y , Zhang C , Luo L , Ma Y , Liu J
Ref : Toxicology , :152934 , 2021
Abstract : Acrylamide (ACR) is a recognized toxin that is known to induce neurotoxicity in humans and experimental animals. This study aimed to investigate the toxic effects of subacute exposure of the motor endplate (MEP) of the gastrocnemius in rats to ACR. All rats were randomly divided into control, 9, 18, and 36 mg/kg ACR groups, and ACR was administered by gastric gavage for 21 days. The behavioral tests were performed weekly. On the 22(nd) day, the wet weight of the gastrocnemius was measured. The changes in muscle fiber structure, nerve endings, and MEP in the gastrocnemius were examined by hematoxylin-eosin (HE) and gold chloride staining. Acetylcholinesterase (AChE) content in the gastrocnemius was detected by AChE staining. The expression of AChE and calcitonin gene-related peptide was detected by immunohistochemistry and western blot. Rats exposed to ACR showed a significant increase in gait scores and hind limb splay distance compared with the control group, and the wet weight of the gastrocnemius was reduced, HE staining showed that the muscle fiber structure of the gastrocnemius became thin and the arrangement was dense with nuclear aggregation, gold chloride staining showed that nerve branches decreased and became thin, nerve fibers became short and light, the number of MEPs was decreased, the staining became light, and the structure was not clear. AChE staining showed that the number of MEPs was significantly reduced after exposure to ACR, the shape became small, and the AChE content decreased in a dose-dependent manner. Immunohistochemistry and western blot analysis results of the expression levels of AchE and CGRP showed a decreasing trend as compared to the control group with increasing ACR exposure dose. The reduction in protein levels may be the mechanism by which ACR has a toxic effect on the MEP in the gastrocnemius of rats.
ESTHER : Yanxian_2021_Toxicology__152934
PubMedSearch : Yanxian_2021_Toxicology__152934
PubMedID: 34509579

Title : Soluble Epoxide Hydrolase Deletion Attenuated Nicotine-induced Arterial Stiffness via Limiting the Loss of SIRT1 - Hu_2021_Am.J.Physiol.Heart.Circ.Physiol__
Author(s) : Hu S , Luo J , Fu M , Luo L , Cai Y , Li W , Li Y , Dong R , Yang Y , Tu L , Xu X
Ref : American Journal of Physiology Heart Circ Physiol , : , 2021
Abstract : Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2(-/-)) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide (NAM, SIRT1 inhibitor) simultaneously for four weeks. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2(-/-) mice without NAM treatment. However, the arterial protective effects were gone in Ephx2(-/-) mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced MMP2 upregulation via SIRT1-mediated YAP deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.
ESTHER : Hu_2021_Am.J.Physiol.Heart.Circ.Physiol__
PubMedSearch : Hu_2021_Am.J.Physiol.Heart.Circ.Physiol__
PubMedID: 34142887

Title : Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease - Luo_2020_Bioorg.Med.Chem__115400
Author(s) : Luo L , Song Q , Li Y , Cao Z , Qiang X , Tan Z , Deng Y
Ref : Bioorganic & Medicinal Chemistry , :115400 , 2020
Abstract : A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Abeta1-42 aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC50=2.66nM), which was significantly better than Donepezil (IC50=26.4nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.
ESTHER : Luo_2020_Bioorg.Med.Chem__115400
PubMedSearch : Luo_2020_Bioorg.Med.Chem__115400
PubMedID: 32146060

Title : Multitarget drug design strategy against Alzheimer's disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties - Li_2017_Bioorg.Med.Chem_25_714
Author(s) : Li Y , Qiang X , Luo L , Yang X , Xiao G , Zheng Y , Cao Z , Sang Z , Su F , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 25 :714 , 2017
Abstract : A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50=2.49+/-0.08nM and 1.74+/-0.0581muM, respectively), good self- and Cu2+-induced Abeta1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.
ESTHER : Li_2017_Bioorg.Med.Chem_25_714
PubMedSearch : Li_2017_Bioorg.Med.Chem_25_714
PubMedID: 27923535

Title : Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer's disease - Yang_2017_Bioorg.Chem_71_305
Author(s) : Yang X , Qiang X , Li Y , Luo L , Xu R , Zheng Y , Cao Z , Tan Z , Deng Y
Ref : Bioorg Chem , 71 :305 , 2017
Abstract : A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC50 values of 2.11muM and 1.56muM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50 value of 2.68muM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
ESTHER : Yang_2017_Bioorg.Chem_71_305
PubMedSearch : Yang_2017_Bioorg.Chem_71_305
PubMedID: 28267984

Title : Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease - Xiao_2017_Bioorg.Med.Chem_25_1030
Author(s) : Xiao G , Li Y , Qiang X , Xu R , Zheng Y , Cao Z , Luo L , Yang X , Sang Z , Su F , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 25 :1030 , 2017
Abstract : A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91muM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Abeta1-42 aggregation and Cu2+-induced Abeta1-42 aggregation by 89.5% and 79.7% at 25muM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29muM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
ESTHER : Xiao_2017_Bioorg.Med.Chem_25_1030
PubMedSearch : Xiao_2017_Bioorg.Med.Chem_25_1030
PubMedID: 28011206

Title : Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and beta-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease - Luo_2017_Bioorg.Med.Chem_25_1997
Author(s) : Luo L , Li Y , Qiang X , Cao Z , Xu R , Yang X , Xiao G , Song Q , Tan Z , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 25 :1997 , 2017
Abstract : A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu2+-induced Abeta1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50=0.59+/-0.02muM), MAO-A and MAO-B (IC50=1.01+/-0.02muM and 0.90+/-0.01muM respectively), excellent efficiency to block both self- and Cu2+-induced Abeta1-42 aggregation (74.8+/-1.2% and 87.7+/-1.9% at 25muM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.
ESTHER : Luo_2017_Bioorg.Med.Chem_25_1997
PubMedSearch : Luo_2017_Bioorg.Med.Chem_25_1997
PubMedID: 28237559

Title : Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-beta-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer's disease - Li_2016_Eur.J.Med.Chem_126_762
Author(s) : Li Y , Qiang X , Luo L , Yang X , Xiao G , Liu Q , Ai J , Tan Z , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 126 :762 , 2016
Abstract : A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC50 = 0.00878 +/- 0.0002 muM, 0.0212 +/- 0.006 muM and 0.0371 +/- 0.004 muM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+-induced Abeta1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD.
ESTHER : Li_2016_Eur.J.Med.Chem_126_762
PubMedSearch : Li_2016_Eur.J.Med.Chem_126_762
PubMedID: 27951485

Title : A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Abeta25-35-impaired mouse cognitive function - Zhang_2016_Psychopharmacology.(Berl)_233_599
Author(s) : Zhang Z , Chen R , An W , Wang C , Liao G , Dong X , Bi A , Yin Z , Luo L
Ref : Psychopharmacology (Berl) , 233 :599 , 2016
Abstract : RATIONALE: The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy. OBJECTIVES: We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Abeta25-35-injected mice, and the potential mechanisms.
METHODS: AChE activity assay, intracellular Ca(2+) content and calcium currents measurement, and Abeta25-35-induced cellular death determine were performed for validation of designed targets and neuroprotection of SCR-1693. Mice were orally administrated with SCR-1693 once daily after an Abeta25-35 injection. The Morris water maze and Y-maze test, and hippocampal protein detection were conducted on days 5-10, day 11, and day 8. The pyramidal neuron number, hippocampal AChE activity, and synaptic transmission were measured on day 12.
RESULTS: SCR-1693 acted as a selective, reversible, and noncompetitive inhibitor of AChE, and a nonselective voltage-gated calcium channel blocker. SCR-1693 also inhibited the increase of AChE activity in the mouse hippocampus. SCR-1693 was more effective than donepezil and memantine in preventing Abeta25-35-induced long-term and short-term memory impairment, maintaining the basal transmission of Schaffer collateral-CA1 synapses, and sustaining LTP in mouse hippocampus. SCR-1693 attenuated Abeta25-35-induced death of SH-SY5Y cell and the loss of hippocampal pyramidal neurons, and regulated Abeta25-35-induced signal cascade in neurons.
CONCLUSIONS: All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.
ESTHER : Zhang_2016_Psychopharmacology.(Berl)_233_599
PubMedSearch : Zhang_2016_Psychopharmacology.(Berl)_233_599
PubMedID: 26554390

Title : Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-beta-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease - Li_2016_Bioorg.Med.Chem.Lett_26_2035
Author(s) : Li Y , Qiang X , Yang X , Luo L , Xiao G , Cao Z , Tan Z , Deng Y
Ref : Bioorganic & Medicinal Chemistry Lett , 26 :2035 , 2016
Abstract : A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Abeta1-42 aggregation and HuAChE-induced Abeta1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06muM) and good inhibition of BuChE (IC50=28.04muM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Abeta aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
ESTHER : Li_2016_Bioorg.Med.Chem.Lett_26_2035
PubMedSearch : Li_2016_Bioorg.Med.Chem.Lett_26_2035
PubMedID: 26947607

Title : Genome sequencing of adzuki bean (Vigna angularis) provides insight into high starch and low fat accumulation and domestication - Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
Author(s) : Yang K , Tian Z , Chen C , Luo L , Zhao B , Wang Z , Yu L , Li Y , Sun Y , Li W , Chen Y , Zhang Y , Ai D , Zhao J , Shang C , Ma Y , Wu B , Wang M , Gao L , Sun D , Zhang P , Guo F , Wang W , Wang J , Varshney RK , Ling HQ , Wan P
Ref : Proc Natl Acad Sci U S A , 112 :13213 , 2015
Abstract : Adzuki bean (Vigna angularis), an important legume crop, is grown in more than 30 countries of the world. The seed of adzuki bean, as an important source of starch, digestible protein, mineral elements, and vitamins, is widely used foods for at least a billion people. Here, we generated a high-quality draft genome sequence of adzuki bean by whole-genome shotgun sequencing. The assembled contig sequences reached to 450 Mb (83% of the genome) with an N50 of 38 kb, and the total scaffold sequences were 466.7 Mb with an N50 of 1.29 Mb. Of them, 372.9 Mb of scaffold sequences were assigned to the 11 chromosomes of adzuki bean by using a single nucleotide polymorphism genetic map. A total of 34,183 protein-coding genes were predicted. Functional analysis revealed that significant differences in starch and fat content between adzuki bean and soybean were likely due to transcriptional abundance, rather than copy number variations, of the genes related to starch and oil synthesis. We detected strong selection signals in domestication by the population analysis of 50 accessions including 11 wild, 11 semiwild, 17 landraces, and 11 improved varieties. In addition, the semiwild accessions were illuminated to have a closer relationship to the cultigen accessions than the wild type, suggesting that the semiwild adzuki bean might be a preliminary landrace and play some roles in the adzuki bean domestication. The genome sequence of adzuki bean will facilitate the identification of agronomically important genes and accelerate the improvement of adzuki bean.
ESTHER : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
PubMedSearch : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213
PubMedID: 26460024
Gene_locus related to this paper: phaan-a0a0l9ttq5 , phaan-a0a0l9vh69 , phaan-a0a0l9vh89 , phaan-a0a0s3tc53 , vigrr-a0a1s3v914 , phaan-a0a0s3s998 , phaan-a0a0s3siv8 , phaan-a0a0l9uys5 , phaan-a0a0s3rp07 , phaan-a0a0s3rbq0 , vigrr-a0a1s3tul4 , phaan-a0a0s3smk7 , phaan-a0a0s3slm9 , phaan-a0a0l9ujf5 , phaan-a0a0l9til9 , phaan-a0a0l9uqr2 , phaan-a0a0l9v1m8 , phaan-a0a0l9uc60 , phaan-a0a0l9ucr8

Title : Calsyntenin-3 molecular architecture and interaction with neurexin 1alpha - Lu_2014_J.Biol.Chem_289_34530
Author(s) : Lu Z , Wang Y , Chen F , Tong H , Reddy MV , Luo L , Seshadrinathan S , Zhang L , Holthauzen LM , Craig AM , Ren G , Rudenko G
Ref : Journal of Biological Chemistry , 289 :34530 , 2014
Abstract : Calsyntenin 3 (Cstn3 or Clstn3), a recently identified synaptic organizer, promotes the development of synapses. Cstn3 localizes to the postsynaptic membrane and triggers presynaptic differentiation. Calsyntenin members play an evolutionarily conserved role in memory and learning. Cstn3 was recently shown in cell-based assays to interact with neurexin 1alpha (n1alpha), a synaptic organizer that is implicated in neuropsychiatric disease. Interaction would permit Cstn3 and n1alpha to form a trans-synaptic complex and promote synaptic differentiation. However, it is contentious whether Cstn3 binds n1alpha directly. To understand the structure and function of Cstn3, we determined its architecture by electron microscopy and delineated the interaction between Cstn3 and n1alpha biochemically and biophysically. We show that Cstn3 ectodomains form monomers as well as tetramers that are stabilized by disulfide bonds and Ca(2+), and both are probably flexible in solution. We show further that the extracellular domains of Cstn3 and n1alpha interact directly and that both Cstn3 monomers and tetramers bind n1alpha with nanomolar affinity. The interaction is promoted by Ca(2+) and requires minimally the LNS domain of Cstn3. Furthermore, Cstn3 uses a fundamentally different mechanism to bind n1alpha compared with other neurexin partners, such as the synaptic organizer neuroligin 2, because Cstn3 does not strictly require the sixth LNS domain of n1alpha. Our structural data suggest how Cstn3 as a synaptic organizer on the postsynaptic membrane, particularly in tetrameric form, may assemble radially symmetric trans-synaptic bridges with the presynaptic synaptic organizer n1alpha to recruit and spatially organize proteins into networks essential for synaptic function.
ESTHER : Lu_2014_J.Biol.Chem_289_34530
PubMedSearch : Lu_2014_J.Biol.Chem_289_34530
PubMedID: 25352602

Title : A combined transgenic proteomic analysis and regulated trafficking of neuroligin-2 - Kang_2014_J.Biol.Chem_289_29350
Author(s) : Kang Y , Ge Y , Cassidy RM , Lam V , Luo L , Moon KM , Lewis R , Molday RS , Wong RO , Foster LJ , Craig AM
Ref : Journal of Biological Chemistry , 289 :29350 , 2014
Abstract : Synapses, the basic units of communication in the brain, require complex molecular machinery for neurotransmitter release and reception. Whereas numerous components of excitatory postsynaptic sites have been identified, relatively few proteins are known that function at inhibitory postsynaptic sites. One such component is neuroligin-2 (NL2), an inhibitory synapse-specific cell surface protein that functions in cell adhesion and synaptic organization via binding to neurexins. In this study, we used a transgenic tandem affinity purification and mass spectrometry strategy to isolate and characterize NL2-associated complexes. Complexes purified from brains of transgenic His6-FLAG-YFP-NL2 mice showed enrichment in the Gene Ontology terms cell-cell signaling and synaptic transmission relative to complexes purified from wild type mice as a negative control. In addition to expected components including GABA receptor subunits and gephyrin, several novel proteins were isolated in association with NL2. Based on the presence of multiple components involved in trafficking and endocytosis, we showed that NL2 undergoes dynamin-dependent endocytosis in response to soluble ligand and colocalizes with VPS35 retromer in endosomes. Inhibitory synapses in brain also present a particular challenge for imaging. Whereas excitatory synapses on spines can be imaged with a fluorescent cell fill, inhibitory synapses require a molecular tag. We find the His6-FLAG-YFP-NL2 to be a suitable tag, with the unamplified YFP signal localizing appropriately to inhibitory synapses in multiple brain regions including cortex, hippocampus, thalamus, and basal ganglia. Altogether, we characterize NL2-associated complexes, demonstrate regulated trafficking of NL2, and provide tools for further proteomic and imaging studies of inhibitory synapses.
ESTHER : Kang_2014_J.Biol.Chem_289_29350
PubMedSearch : Kang_2014_J.Biol.Chem_289_29350
PubMedID: 25190809

Title : The Specific alpha-Neurexin Interactor Calsyntenin-3 Promotes Excitatory and Inhibitory Synapse Development - Pettem_2013_Neuron_80_113
Author(s) : Pettem KL , Yokomaku D , Luo L , Linhoff MW , Prasad T , Connor SA , Siddiqui TJ , Kawabe H , Chen F , Zhang L , Rudenko G , Wang YT , Brose N , Craig AM
Ref : Neuron , 80 :113 , 2013
Abstract : Perturbations of cell surface synapse-organizing proteins, particularly alpha-neurexins, contribute to neurodevelopmental and psychiatric disorders. From an unbiased screen, we identify calsyntenin-3 (alcadein-beta) as a synapse-organizing protein unique in binding and recruiting alpha-neurexins, but not beta-neurexins. Calsyntenin-3 is present in many pyramidal neurons throughout cortex and hippocampus but is most highly expressed in interneurons. The transmembrane form of calsyntenin-3 can trigger excitatory and inhibitory presynapse differentiation in contacting axons. However, calsyntenin-3-shed ectodomain, which represents about half the calsyntenin-3 pool in brain, suppresses the ability of multiple alpha-neurexin partners including neuroligin 2 and LRRTM2 to induce presynapse differentiation. Clstn3-/- mice show reductions in excitatory and inhibitory synapse density by confocal and electron microscopy and corresponding deficits in synaptic transmission. These results identify calsyntenin-3 as an alpha-neurexin-specific binding partner required for normal functional GABAergic and glutamatergic synapse development.
ESTHER : Pettem_2013_Neuron_80_113
PubMedSearch : Pettem_2013_Neuron_80_113
PubMedID: 24094106

Title : The oyster genome reveals stress adaptation and complexity of shell formation - Zhang_2012_Nature_490_49
Author(s) : Zhang G , Fang X , Guo X , Li L , Luo R , Xu F , Yang P , Zhang L , Wang X , Qi H , Xiong Z , Que H , Xie Y , Holland PW , Paps J , Zhu Y , Wu F , Chen Y , Wang J , Peng C , Meng J , Yang L , Liu J , Wen B , Zhang N , Huang Z , Zhu Q , Feng Y , Mount A , Hedgecock D , Xu Z , Liu Y , Domazet-Loso T , Du Y , Sun X , Zhang S , Liu B , Cheng P , Jiang X , Li J , Fan D , Wang W , Fu W , Wang T , Wang B , Zhang J , Peng Z , Li Y , Li N , Chen M , He Y , Tan F , Song X , Zheng Q , Huang R , Yang H , Du X , Chen L , Yang M , Gaffney PM , Wang S , Luo L , She Z , Ming Y , Huang W , Huang B , Zhang Y , Qu T , Ni P , Miao G , Wang Q , Steinberg CE , Wang H , Qian L , Liu X , Yin Y
Ref : Nature , 490 :49 , 2012
Abstract : The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.
ESTHER : Zhang_2012_Nature_490_49
PubMedSearch : Zhang_2012_Nature_490_49
PubMedID: 22992520
Gene_locus related to this paper: cragi-k1qzk7 , cragi-k1rad0 , cragi-k1p6v9 , cragi-k1pa46 , cragi-k1pga2 , cragi-k1pp63 , cragi-k1pwa8 , cragi-k1q0b1.1 , cragi-k1q0b1.2 , cragi-k1q1h2 , cragi-k1q2z6 , cragi-k1qaj8 , cragi-k1qaw5 , cragi-k1qhl5 , cragi-k1qly1 , cragi-k1qqb1.1 , cragi-k1qqb1.2 , cragi-k1qs61 , cragi-k1qs99 , cragi-k1qwl6 , cragi-k1r068 , cragi-k1r0n3.1 , cragi-k1r0n3.2 , cragi-k1r0r4 , cragi-k1r1i9 , cragi-k1r8q9 , cragi-k1rgi1 , cragi-k1rig4 , cragi-k1s0a7.1 , cragi-k1s0a7.2 , cragi-k1s0a7.3 , cragi-k1q6q0 , cragi-k1rru1 , cragi-k1qfi4 , cragi-k1qvm5 , cragi-k1qq58 , cragi-k1qdc0 , cragi-k1r754 , cragi-k1pje5 , cragi-k1qca6 , cragi-k1qdt5 , cragi-k1qkz7 , cragi-k1rgd2 , cragi-k1puh6 , cragi-k1raz4 , cragi-k1qqj4 , cragi-k1rbs1

Title : Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice - Mosca_2012_Nature_484_237
Author(s) : Mosca TJ , Hong W , Dani VS , Favaloro V , Luo L
Ref : Nature , 484 :237 , 2012
Abstract : Synapse assembly requires trans-synaptic signals between the pre- and postsynapse, but our understanding of the essential organizational molecules involved in this process remains incomplete. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with alpha-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection.
ESTHER : Mosca_2012_Nature_484_237
PubMedSearch : Mosca_2012_Nature_484_237
PubMedID: 22426000

Title : Natural variation in GS5 plays an important role in regulating grain size and yield in rice - Li_2011_Nat.Genet_43_1266
Author(s) : Li Y , Fan C , Xing Y , Jiang Y , Luo L , Sun L , Shao D , Xu C , Li X , Xiao J , He Y , Zhang Q
Ref : Nat Genet , 43 :1266 , 2011
Abstract : Increasing crop yield is one of the most important goals of plant science research. Grain size is a major determinant of grain yield in cereals and is a target trait for both domestication and artificial breeding(1). We showed that the quantitative trait locus (QTL) GS5 in rice controls grain size by regulating grain width, filling and weight. GS5 encodes a putative serine carboxypeptidase and functions as a positive regulator of grain size, such that higher expression of GS5 is correlated with larger grain size. Sequencing of the promoter region in 51 rice accessions from a wide geographic range identified three haplotypes that seem to be associated with grain width. The results suggest that natural variation in GS5 contributes to grain size diversity in rice and may be useful in improving yield in rice and, potentially, other crops(2).
ESTHER : Li_2011_Nat.Genet_43_1266
PubMedSearch : Li_2011_Nat.Genet_43_1266
PubMedID: 22019783
Gene_locus related to this paper: orysa-q5w727

Title : Effects of Pb2+ on muscarinic modulation of glutamatergic synaptic transmission in rat hippocampal CA1 area - Wang_2007_Neurotoxicol_28_499
Author(s) : Wang L , Luo L , Luo YY , Gu Y , Ruan DY
Ref : Neurotoxicology , 28 :499 , 2007
Abstract : Lead (Pb(2+)) is a pollutant commonly found in the environment. It causes a wide variety of detrimental effects on developing central nervous system. However, the mechanisms of its neurotoxicity remained to be elucidated. In hippocampus, the muscarinic cholinergic system modulates certain forms of synaptic transmission and plasticity, and plays an important role in learning and memory. In this study, the effects of Pb(2+) on muscarinic modulation of glutamatergic synaptic transmission in hippocampal CA1 area were investigated using the conventional whole-cell patch-clamp technique in rat hippocampal slices. In the presence of nicotinic antagonist mecamylamine, carbachol (CCh), a cholinergic agonist, concentration-dependently inhibited glutamatergic excitatory postsynaptic currents (EPSCs), enhanced paired-pulse facilitation (PPF) and the response to 10-Hz pulse-trains. The analysis of the spontaneous excitatory postsynaptic currents (sEPSCs) showed the activation of muscarinic receptors by CCh decreased the frequency, amplitude and decay time of sEPSCs. The 10 microM Pb(2+) depressed the inhibition of EPSCs by CCh, reduced the CCh-induced enhancement of PPF and the response to 10-Hz pulse-trains, and also affected the modulation of sEPSCs by CCh. The results suggested that the activation of muscarinic acetylcholine (ACh) receptors in hippocampus could modulate glutamatergic synaptic transmission, while Pb(2+) exposure would lead to an alteration of muscarinic modulation, which might be involved in the Pb(2+)-induced impairment of synaptic transmission and plasticity during learning and memory.
ESTHER : Wang_2007_Neurotoxicol_28_499
PubMedSearch : Wang_2007_Neurotoxicol_28_499
PubMedID: 17267040

Title : [Effect of resveratrol on the cognitive ability of Alzheimeros mice] - Luo_2006_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_31_566
Author(s) : Luo L , Huang YM
Ref : Zhong Nan Da Xue Xue Bao Yi Xue Ban , 31 :566 , 2006
Abstract : OBJECTIVE: To explore the effect of resveratrol on the cognition of Alzheimer's mice (AD) and its mechanism, and to assess its action on the reproduction system.
METHODS: According to the results of step-down test, 84 Kunming female mice were randomly divided into 6 groups: Group A [sham operated+1% CMC-Na (0.01 mL/g)], Group B [ovariectomy+D-galactose+1% CMC-Na (0.01 mL/g)], Group C [ovariectomy+D-galactose+0.05 mg/(kg.d) Diethylstilbestrol], Group D [ovariectomy+D-galactose+15 mg/(kg.d) Res], and Group E [ovariectomy+D-galactose injected+45 mg/(kg.d) Res], and Group F [ovariectomy+D-galactose +135 mg/(kg.d) Res]. Experimental cycle was 60 days.
RESULTS: Resveratrol of every dosage could improve the performance records of behavior tests in AD mice,could inhibit the SOD vitality and the MDA level both in the serum and in the brain, and could suppress the acetylcholinesterase vitality and the bax expression. Resveratrol has no endometrial hyperplasia effect. CONCLUSION: Resveratrol can improve the cognitive ability of AD mice, which may contribute to the resveratrol's antioxidation and antiapoptosis, and can modulate acetylcholinesterase. Resveratrol has no side-effect of endometrial hyperplasia on AD mice.
ESTHER : Luo_2006_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_31_566
PubMedSearch : Luo_2006_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_31_566
PubMedID: 16951520

Title : The strength of dehalogenase-substrate hydrogen bonding correlates with the rate of Meisenheimer intermediate formation - Dong_2003_Biochemistry_42_9482
Author(s) : Dong J , Lu X , Wei Y , Luo L , Dunaway-Mariano D , Carey PR
Ref : Biochemistry , 42 :9482 , 2003
Abstract : 4-Chlorobenzoyl-coenzyme A (4-CBA-CoA) dehalogenase catalyzes the hydrolytic dehalogenation of 4-CBA-CoA to 4-hydroxybenzoyl-CoA by using an active site aspartate as the nucleophile. Formation of the corresponding Meisenheimer complex (EMc) is followed by chloride ion expulsion which forms the arylated intermediate (EAr). This is then hydrolyzed to the product. In this paper, we explore the relationship between active site polarizing forces acting on the benzoyl carbonyl and the rate of formation of the Meisenheimer complex. The polarizing forces at the C[double bond]O group were modulated by introducing site-selected mutations (A112V, Y65D, G113A, G113S, G113N, and F64P), near the C[double bond]O binding site. Using either the substrate, 4-CBA-CoA, or the substrate analogue, 4-methylbenzoyl-CoA (4-MBA-CoA), Raman difference spectroscopy provided the position of the C[double bond]O stretching frequency (nu(C)[double bond](O)) for a total of 10 enzyme-ligand complexes. In turn, the values of the C[double bond]O frequencies could be converted to differences in effective hydrogen bonding strengths between members of the series, based on earlier model studies [Clarkson, J., Tonge, P. J., Taylor, K. L., Dunaway-Mariano, D., and Carey, P. (1997) Biochemistry 36, 10192-10199]. Catalysis in the F64P, G113A, G113S, and G113N dehalogenase mutants was very slow with k(cat) values ranging from 8 x 10(-3) to 7.6 x 10(-6) s(-1). The EAr intermediate did not accumulate to a detectable level on these enzymes during a single turnover. Catalysis in the Y65D and A112V dehalogenase mutants were almost as efficient as catalysis in wild-type dehalogenase with k(cat) values of 0.1-0.6 s(-1). In wild-type dehalogenase, 22% of the bound substrate accumulated as the EAr intermediate during a single turnover (k(obs) for EAr formation = 24 s(-(1)); in the Y65D mutant, the level of accumulation is 17% (k(obs) for EAr formation = 3 s(-1)), and in the A112V mutant, the level is 23% (k(obs) for EAr formation = 17 s(-1)). The k(obs) for EAr formation in wild-type dehalogenase and the more active dehalogenase mutants (Y65D and A112V) was taken to be an estimate of the k for EMc formation, and the k(obs) for EP formation in a single turnover was taken to be an estimate of the k for EMc formation in the severely impaired mutants (F64P, G113A, G113S, and G113N). A plot of the log k(obs) for EMc formation versus the C[double bond]O stretching frequency of bound 4-CBA-CoA (or 4-MBA-CoA) is a straight line (R(2) = 0.9584). Throughout the series, nu(C)[double bond](O) varied by 61 cm(-1), corresponding to the change in hydrogen bonding enthalpy of 67 kJ/mol. The results show that changes in polarizing forces at the benzoyl carbonyl are transmitted to the benzoyl (4) position and correlate with the rate of aromatic nucleophilic addition five chemical bonds away. Interestingly, the relationship between effective polarizing forces and reactivity seen here for dehalogenase is similar to that reported for the addition-elimination reaction involving the hydrolysis of a series of acyl serine proteases.
ESTHER : Dong_2003_Biochemistry_42_9482
PubMedSearch : Dong_2003_Biochemistry_42_9482
PubMedID: 12899635