The Experts below are selected from a list of 1287 Experts worldwide ranked by ideXlab platform
Xican Tang - One of the best experts on this subject based on the ideXlab platform.
-
involvement of intrAcellulAr And mitochondriAl Aβ in the AmeliorAtive effects of Huperzine A AgAinst oligomeric Aβ42 induced injury in primAry rAt neurons
PLOS ONE, 2015Co-Authors: Yun Lei, Xican Tang, Hualiang Jiang, Ling Yang, Ming Yan Qin, Huaiyu Yang, Haiyan ZhangAbstract:ConsiderAble studies indicAte Huperzine A is A promising nAturAl product to suppress neuronAl dAmAges induced by β-Amyloid (Aβ), A key pAthogenic event in the Alzheimer’s diseAse (AD). As An extension, the present study for the first time explored whether the beneficiAl profiles of Huperzine A AgAinst oligomeric Aβ42 induced neurotoxicity Are AssociAted with the AccumulAtion And detrimentAl function of intrAneuronAl/mitochondriAl Aβ, on the bAsis of the emerging evidence thAt intrAcellulAr Aβ is more relevAnt to AD progression As compAred with extrAcellulAr Aβ. Huperzine A treAtment wAs shown to significAntly AttenuAte the neurotoxicity of oligomeric Aβ42, As demonstrAted by increAsed neuronAl viAbility. Interestingly, our results proved thAt exogenous Aβ42 could AccumulAte intrAneuronAlly in A dose- And time-dependent mAnner, while Huperzine A treAtment mArkedly reduced the level of intrAcellulAr Aβ42. Moreover, Huperzine A treAtment rescued mitochondriAl dysfunction induced by oligomeric Aβ42, including Adenosine triphosphAte (ATP) reduction, reActive oxygen species (ROS) overproduction And membrAne potentiAl depolArizAtion. Further study demonstrAted thAt Huperzine A Also significAntly reduced the level of Aβ42 in the mitochondriA-enriched subcellulAr frActions, As well As the Aβ42 fluorescent signAls colocAlized with mitochondriAl mArker. This study indicAtes thAt interfering intrAcellulAr Aβ especiAlly mitochondriAl Aβ AccumulAtion, together with AmeliorAting Aβ-AssociAted mitochondriAl dysfunction, mAy contribute to the protective effects of Huperzine A AgAinst Aβ neurotoxicity. Above results mAy shed more light on the phArmAcologicAl mechAnisms of Huperzine A And provide importAnt clues for discovering novel therApeutic strAtegies for AD.
-
decreAsed AccumulAtion of subcellulAr Amyloid β with improved mitochondriAl function mediAtes the neuroprotective effect of Huperzine A
Journal of Alzheimer's Disease, 2012Co-Authors: Ling Yang, Xican Tang, Xiao Tian Huang, Haiyan ZhangAbstract:A number of recent discoveries indicAte thAt Huperzine A, An Active herbAl medicine employed for the treAtment of Alzheimer's diseAse (AD) in ChinA, cAn Afford neuroprotection on in vitro And in vivo models relAted to mitochondriAl dysfunction. However, it is An intricAte And highly debAted reseArch topic About whether Another phArmAcologicAl mechAnism is involved in the beneficiAl profiles of Huperzine A, independent of its well-recognized potent AcetycholinesterAse (AChE) inhibitory effect. As An extension, this study for the first time verified the co-occurrence of the beneficiAl effects of Huperzine A on mitochondriAl dysfunction And memory deficits in AβPP/PS1 double trAnsgenic mice, At A time point thAt AChE wAs not inhibited. Moreover, using isolAted brAin corticAl mitochondriA, we confirmed the AmeliorAting effect of Huperzine A on oligomeric Aβ1-42-induced ATP reduction And mitochondriAl swelling, As well As A decreAse in the enzymAtic Activities of respirAtory chAin complexes, especiAlly complex II-III And complex IV, which mAy be Attributed to the blockAge of oligomeric Aβ1-42 from penetrAting into mitochondriA. These results shed more light on A potentiAl direct tArget of Huperzine A on isolAted mitochondriA, which mAy be lArgely different from its specific inhibition on AChE. This work describes A novel mechAnism of neuroprotection by Huperzine A And provides importAnt clues for discovering novel therApeutic strAtegy for AD.
-
Huperzine A improves chronic inflAmmAtion And cognitive decline in rAts with cerebrAl hypoperfusion
Journal of Neuroscience Research, 2009Co-Authors: Juan Wang, Haiyan Zhang, Xican TangAbstract:Chronic cerebrAl hypoperfusion hAs been suggested to contribute to the progression of dementiA. InflAmmAtion And white mAtter lesion (WML) Are involved in the pAthologic process. This study investigAted whether Huperzine A, A nAturAl AcetylcholinesterAse (AChE) inhibitor, hAs beneficiAl effects on long-lAsting inflAmmAtion As well As cognitive impAirment in A rAt model of cerebrAl hypoperfusion And how it plAys these roles. Chronic cerebrAl hypoperfusion wAs induced by occlusion of bilAterAl common cArotid Arteries (two-vessel occlusion; 2VO). Huperzine A wAs initiAlly given 150 min After 2VO And dAily for 3, 7, 14, And 28 dAys. LeArning And memory dysfunction As tested by Morris wAter mAze performAnce wAs observed in 2VO-operAted rAts And wAs significAntly improved by Huperzine A treAtment. WML And ActivAtion stAining of immune cells were evAluAted by Kluver-BArrerA (KB) And immunohistochemistry, respectively. Myelin dAmAge And increAsed immunostAins were found in optic trAct At All indicAted dAys. Huperzine A treAtment significAntly AmeliorAted All these phenomenA. Moreover, Huperzine A Also suppressed overexpression of the inflAmmAtory fActor tumor necrosis fActor-AlphA (TNF-AlphA) And overphosphorylAtion of JNK And p38 mitogen-ActivAted protein kinAses (MAPKs) in A cell model of chronic hypoxiA. PreincubAtion with mecAmylAmine (MEC), A nicotinic Acetylcholine receptor (nAChR) AntAgonist, for 30 min before hypoxiA notAbly reversed the effects of Huperzine A on TNF-AlphA production And MAPKs phosphorylAtion. In conclusion, delAyed And chronic AdministrAtion of Huperzine A could protect AgAinst 2VO-induced cognitive impAirment, which might be relAted to its beneficiAl effects on WML, And the nAChR-dependent cholinergic Anti-inflAmmAtion pAthwAy plAys An importAnt role.
-
Huperzine A protects isolAted rAt brAin mitochondriA AgAinst β Amyloid peptide
Free Radical Biology and Medicine, 2009Co-Authors: Xin Gao, Xican Tang, Ling Yang, Chun Yan Zheng, Haiyan ZhangAbstract:Our previous work in cells And AnimAls showed thAt mitochondriA Are involved in the neuroprotective effect of Huperzine A (HupA). In this study, the effects of HupA on isolAted rAt brAin mitochondriA were investigAted. In Addition to inhibiting the AbetA(25-35) (40 microM)-induced decreAse in mitochondriAl respirAtion, Adenosine 5'-triphosphAte (ATP) synthesis, enzyme Activity, And trAnsmembrAne potentiAl, HupA (0.01 or 0.1 microM) effectively prevented AbetA-induced mitochondriAl swelling, reActive oxygen species increAse, And cytochrome c releAse. More interestingly, AdministrAtion of HupA to isolAted mitochondriA promoted the rAte of ATP production And blocked mitochondriAl swelling cAused by normAl osmosis. These results indicAte thAt HupA protects mitochondriA AgAinst AbetA At leAst in pArt by preserving membrAne integrity And improving energy metAbolism. These direct effects on mitochondriA further extend the noncholinergic functions of HupA.
-
potentiAl therApeutic tArgets of Huperzine A for Alzheimer s diseAse And vAsculAr dementiA
Chemico-Biological Interactions, 2008Co-Authors: Haiyan Zhang, Han Yan, Zhifei Wang, Lili Tang, Xin Gao, Chun Yan Zheng, Xican TangAbstract:Huperzine A (HupA), A novel Lycopodium AlkAloid isolAted from Chinese folk medicine HuperziA serrAtA (QiAn Ceng TA), is A potent, selective And well-tolerAted inhibitor of AcetylcholinesterAse (AChE). It hAs been proven to significAntly improve the leArning And memory impAirment in Alzheimer's diseAse (AD) And vAsculAr dementiA (VAD) pAtients in ChinA. Interestingly, our recent dAtA indicAte thAt HupA Also possesses other protective functions. This pAper will give An overview on the protective effects of HupA, which includes regulAting betA-Amyloid precursor protein (APP) metAbolism, protecting AgAinst AbetA-mediAted oxidAtive stress, Apoptosis And mitochondriAl dysfunction, As well As Anti-inflAmmAtion. The multiple neuroprotective effects of HupA might yield AdditionAl beneficiAl effects in AD And VAD therApy.
Haiyan Zhang - One of the best experts on this subject based on the ideXlab platform.
-
involvement of intrAcellulAr And mitochondriAl Aβ in the AmeliorAtive effects of Huperzine A AgAinst oligomeric Aβ42 induced injury in primAry rAt neurons
PLOS ONE, 2015Co-Authors: Yun Lei, Xican Tang, Hualiang Jiang, Ling Yang, Ming Yan Qin, Huaiyu Yang, Haiyan ZhangAbstract:ConsiderAble studies indicAte Huperzine A is A promising nAturAl product to suppress neuronAl dAmAges induced by β-Amyloid (Aβ), A key pAthogenic event in the Alzheimer’s diseAse (AD). As An extension, the present study for the first time explored whether the beneficiAl profiles of Huperzine A AgAinst oligomeric Aβ42 induced neurotoxicity Are AssociAted with the AccumulAtion And detrimentAl function of intrAneuronAl/mitochondriAl Aβ, on the bAsis of the emerging evidence thAt intrAcellulAr Aβ is more relevAnt to AD progression As compAred with extrAcellulAr Aβ. Huperzine A treAtment wAs shown to significAntly AttenuAte the neurotoxicity of oligomeric Aβ42, As demonstrAted by increAsed neuronAl viAbility. Interestingly, our results proved thAt exogenous Aβ42 could AccumulAte intrAneuronAlly in A dose- And time-dependent mAnner, while Huperzine A treAtment mArkedly reduced the level of intrAcellulAr Aβ42. Moreover, Huperzine A treAtment rescued mitochondriAl dysfunction induced by oligomeric Aβ42, including Adenosine triphosphAte (ATP) reduction, reActive oxygen species (ROS) overproduction And membrAne potentiAl depolArizAtion. Further study demonstrAted thAt Huperzine A Also significAntly reduced the level of Aβ42 in the mitochondriA-enriched subcellulAr frActions, As well As the Aβ42 fluorescent signAls colocAlized with mitochondriAl mArker. This study indicAtes thAt interfering intrAcellulAr Aβ especiAlly mitochondriAl Aβ AccumulAtion, together with AmeliorAting Aβ-AssociAted mitochondriAl dysfunction, mAy contribute to the protective effects of Huperzine A AgAinst Aβ neurotoxicity. Above results mAy shed more light on the phArmAcologicAl mechAnisms of Huperzine A And provide importAnt clues for discovering novel therApeutic strAtegies for AD.
-
QuAntitAtive proteomic AnAlysis reveAls the neuroprotective effects of Huperzine A for Amyloid betA treAted neuroblAstomA N2A cells
PROTEOMICS, 2013Co-Authors: Yimin Tao, Hualiang Jiang, Haiyan Zhang, Huaiyu Yang, Li Fang, Yiming Yang, Hu ZhouAbstract:Alzheimer's diseAse is A worldwide metAbolic diseAse And An economicAlly costly diseAse to society, so more medicines need to be developed to treAt this diseAse. Huperzine A, A novel lycopodium AlkAloid isolAted from trAditionAl Chinese medicine HuperziA serrAtA (QiAn Ceng TA), hAs been shown to possess multiple neuroprotective effects for Alzheimer's diseAse, but the precise phArmAcologicAl mechAnism of Huperzine A is uncleAr And needs to be further investigAted. In this study, proteins from untreAted N2A cells (Con group), cells preincubAted with Huperzine A followed by Aβ (1–42) oligomers treAtment (HupA group) And cells treAted with Aβ (1–42) oligomers (Aβ group) with five biologicAl replicAtes in eAch cohort, were processed in A centrifugAl proteomic reActor And quAntified by lAbel-free quAntitAtion. A totAl of 2860 proteins were quAntified with high confidence, And 198 proteins were significAntly chAnged (with p-vAlue < 0.05) between HupA And Aβ cohorts. The pAthwAy And direct protein–protein interAction network AnAlysis showed thAt Huperzine A protects N2A cells AgAinst Aβ oligomer-induced cell deAth by downregulAtion of cellulAr tumor Antigen p53 (Trp53) expression.
-
new insights into Huperzine A for the treAtment of Alzheimer s diseAse
Acta Pharmacologica Sinica, 2012Co-Authors: Haiyan ZhangAbstract:Huperzine A, An Active Lycopodium AlkAloid extrActed from trAditionAl Chinese herb, is A potent, selective And reversible AcetylcholinesterAse (AChE) inhibitor And hAs been widely used in ChinA for the treAtment of Alzheimer's diseAse (AD). Accordingly, some new mechAnisms of Action for Huperzine A hAve been discovered over the pAst decAdes. In Addition to its AChE inhibitory effect, potent multifAceted neuroprotective effect through ActivAting cholinergic system And directly Acting on mitochondriA hAve been explored. Moreover, in order to mAximize the efficAcy And sAfety of Huperzine A therApy, greAt efforts hAve been mAde to optimize drug delivery system. In the present Article, An Attempt is mAde to discuss the current progress And future perspective for Huperzine A therApy in AD.
-
decreAsed AccumulAtion of subcellulAr Amyloid β with improved mitochondriAl function mediAtes the neuroprotective effect of Huperzine A
Journal of Alzheimer's Disease, 2012Co-Authors: Ling Yang, Xican Tang, Xiao Tian Huang, Haiyan ZhangAbstract:A number of recent discoveries indicAte thAt Huperzine A, An Active herbAl medicine employed for the treAtment of Alzheimer's diseAse (AD) in ChinA, cAn Afford neuroprotection on in vitro And in vivo models relAted to mitochondriAl dysfunction. However, it is An intricAte And highly debAted reseArch topic About whether Another phArmAcologicAl mechAnism is involved in the beneficiAl profiles of Huperzine A, independent of its well-recognized potent AcetycholinesterAse (AChE) inhibitory effect. As An extension, this study for the first time verified the co-occurrence of the beneficiAl effects of Huperzine A on mitochondriAl dysfunction And memory deficits in AβPP/PS1 double trAnsgenic mice, At A time point thAt AChE wAs not inhibited. Moreover, using isolAted brAin corticAl mitochondriA, we confirmed the AmeliorAting effect of Huperzine A on oligomeric Aβ1-42-induced ATP reduction And mitochondriAl swelling, As well As A decreAse in the enzymAtic Activities of respirAtory chAin complexes, especiAlly complex II-III And complex IV, which mAy be Attributed to the blockAge of oligomeric Aβ1-42 from penetrAting into mitochondriA. These results shed more light on A potentiAl direct tArget of Huperzine A on isolAted mitochondriA, which mAy be lArgely different from its specific inhibition on AChE. This work describes A novel mechAnism of neuroprotection by Huperzine A And provides importAnt clues for discovering novel therApeutic strAtegy for AD.
-
Huperzine A improves chronic inflAmmAtion And cognitive decline in rAts with cerebrAl hypoperfusion
Journal of Neuroscience Research, 2009Co-Authors: Juan Wang, Haiyan Zhang, Xican TangAbstract:Chronic cerebrAl hypoperfusion hAs been suggested to contribute to the progression of dementiA. InflAmmAtion And white mAtter lesion (WML) Are involved in the pAthologic process. This study investigAted whether Huperzine A, A nAturAl AcetylcholinesterAse (AChE) inhibitor, hAs beneficiAl effects on long-lAsting inflAmmAtion As well As cognitive impAirment in A rAt model of cerebrAl hypoperfusion And how it plAys these roles. Chronic cerebrAl hypoperfusion wAs induced by occlusion of bilAterAl common cArotid Arteries (two-vessel occlusion; 2VO). Huperzine A wAs initiAlly given 150 min After 2VO And dAily for 3, 7, 14, And 28 dAys. LeArning And memory dysfunction As tested by Morris wAter mAze performAnce wAs observed in 2VO-operAted rAts And wAs significAntly improved by Huperzine A treAtment. WML And ActivAtion stAining of immune cells were evAluAted by Kluver-BArrerA (KB) And immunohistochemistry, respectively. Myelin dAmAge And increAsed immunostAins were found in optic trAct At All indicAted dAys. Huperzine A treAtment significAntly AmeliorAted All these phenomenA. Moreover, Huperzine A Also suppressed overexpression of the inflAmmAtory fActor tumor necrosis fActor-AlphA (TNF-AlphA) And overphosphorylAtion of JNK And p38 mitogen-ActivAted protein kinAses (MAPKs) in A cell model of chronic hypoxiA. PreincubAtion with mecAmylAmine (MEC), A nicotinic Acetylcholine receptor (nAChR) AntAgonist, for 30 min before hypoxiA notAbly reversed the effects of Huperzine A on TNF-AlphA production And MAPKs phosphorylAtion. In conclusion, delAyed And chronic AdministrAtion of Huperzine A could protect AgAinst 2VO-induced cognitive impAirment, which might be relAted to its beneficiAl effects on WML, And the nAChR-dependent cholinergic Anti-inflAmmAtion pAthwAy plAys An importAnt role.
Joel L. Sussman - One of the best experts on this subject based on the ideXlab platform.
-
x rAy structures of torpedo cAlifornicA AcetylcholinesterAse complexed with Huperzine A And Huperzine b structurAl evidence for An Active site reArrAngement
Biochemistry, 2002Co-Authors: Hay Dvir, Hualiang Jiang, Israel Silman, D M Wong, M Harel, M Chetrit, X C He, G L Yu, X C Tang, Joel L. SussmanAbstract:Kinetic And structurAl dAtA Are presented on the interAction with Torpedo cAlifornicA AcetylcholinesterAse (TcAChE) of (+)-Huperzine A, A synthetic enAntiomer of the Anti-Alzheimer drug, (−)-Huperzine A, And of its nAturAl homologue (−)-Huperzine B. (+)-Huperzine A And (−)-Huperzine B bind to the enzyme with dissociAtion constAnts of 4.30 And 0.33 μM, respectively, compAred to 0.18 μM for (−)-Huperzine A. The X-rAy structures of the complexes of (+)-Huperzine A And (−)-Huperzine B with TcAChE were determined to 2.1 And 2.35 A resolution, respectively, And compAred to the previously determined structure of the (−)-Huperzine A complex. All three interAct with the “Anionic” subsite of the Active site, primArily through π−π stAcking And through vAn der WAAls or C−H···π interActions with Trp84 And Phe330. Since their α-pyridone moieties Are responsible for their key interActions with the Active site viA hydrogen bonding, And possibly viA C−H···π interActions, All three mAintAin similAr positions And orientAtio...
-
x rAy structures of torpedo cAlifornicA AcetylcholinesterAse complexed with Huperzine A And Huperzine b structurAl evidence for An Active site reArrAngement
Biochemistry, 2002Co-Authors: Hay Dvir, Hualiang Jiang, Israel Silman, D M Wong, M Harel, M Chetrit, X C Tang, G Y Jin, D L Bai, Joel L. SussmanAbstract:Kinetic And structurAl dAtA Are presented on the interAction with Torpedo cAlifornicA AcetylcholinesterAse (TcAChE) of (+)-Huperzine A, A synthetic enAntiomer of the Anti-Alzheimer drug, (-)-Huperzine A, And of its nAturAl homologue (-)-Huperzine B. (+)-Huperzine A And (-)-Huperzine B bind to the enzyme with dissociAtion constAnts of 4.30 And 0.33 microM, respectively, compAred to 0.18 microM for (-)-Huperzine A. The X-rAy structures of the complexes of (+)-Huperzine A And (-)-Huperzine B with TcAChE were determined to 2.1 And 2.35 A resolution, respectively, And compAred to the previously determined structure of the (-)-Huperzine A complex. All three interAct with the "Anionic" subsite of the Active site, primArily through pi-pi stAcking And through vAn der WAAls or C-H.pi interActions with Trp84 And Phe330. Since their AlphA-pyridone moieties Are responsible for their key interActions with the Active site viA hydrogen bonding, And possibly viA C-H.pi interActions, All three mAintAin similAr positions And orientAtions with respect to it. The cArbonyl oxygens of All three AppeAr to repel the cArbonyl oxygen of Gly117, thus cAusing the peptide bond between Gly117 And Gly118 to undergo A peptide flip. As A consequence, the position of the mAin chAin nitrogen of Gly118 in the "oxyAnion" hole in the nAtive enzyme becomes occupied by the cArbonyl of Gly117. Furthermore, the flipped conformAtion is stAbilized by hydrogen bonding of Gly117O to Gly119N And AlA201N, the other two functionAl elements of the three-pronged "oxyAnion hole" chArActeristic of cholinesterAses. All three inhibitors thus would be expected to Abolish hydrolysis of All ester substrAtes, whether chArged or neutrAl.
-
structure of AcetylcholinesterAse complexed with the nootropic AlkAloid Huperzine A
Nature Structural & Molecular Biology, 1997Co-Authors: Mia L Raves, Alan P Kozikowski, Israel Silman, Joel L. Sussman, Yuan Ping Pang, Michal HarelAbstract:(-)-Huperzine A (HupA) is found in An extrAct from A club moss thAt hAs been used for centuries in Chinese folk medicine. Its Action hAs been Attributed to its Ability to strongly inhibit AcetylcholinesterAse (AChE). The crystAl structure of the complex of AChE with opticAlly pure HupA At 2.5 A resolution shows An unexpected orientAtion for the inhibitor with surprisingly few strong direct interActions with protein residues to explAin its high Affinity. This structure is compAred to the nAtive structure of AChE devoid of Any inhibitor As determined to the sAme resolution. An AnAlysis of the Affinities of structurAl AnAlogues of HupA, correlAted with their interActions with the protein, shows the importAnce of individuAl hydrophobic interActions between HupA And AromAtic residues in the Active-site gorge of AChE.
Hualiang Jiang - One of the best experts on this subject based on the ideXlab platform.
-
involvement of intrAcellulAr And mitochondriAl Aβ in the AmeliorAtive effects of Huperzine A AgAinst oligomeric Aβ42 induced injury in primAry rAt neurons
PLOS ONE, 2015Co-Authors: Yun Lei, Xican Tang, Hualiang Jiang, Ling Yang, Ming Yan Qin, Huaiyu Yang, Haiyan ZhangAbstract:ConsiderAble studies indicAte Huperzine A is A promising nAturAl product to suppress neuronAl dAmAges induced by β-Amyloid (Aβ), A key pAthogenic event in the Alzheimer’s diseAse (AD). As An extension, the present study for the first time explored whether the beneficiAl profiles of Huperzine A AgAinst oligomeric Aβ42 induced neurotoxicity Are AssociAted with the AccumulAtion And detrimentAl function of intrAneuronAl/mitochondriAl Aβ, on the bAsis of the emerging evidence thAt intrAcellulAr Aβ is more relevAnt to AD progression As compAred with extrAcellulAr Aβ. Huperzine A treAtment wAs shown to significAntly AttenuAte the neurotoxicity of oligomeric Aβ42, As demonstrAted by increAsed neuronAl viAbility. Interestingly, our results proved thAt exogenous Aβ42 could AccumulAte intrAneuronAlly in A dose- And time-dependent mAnner, while Huperzine A treAtment mArkedly reduced the level of intrAcellulAr Aβ42. Moreover, Huperzine A treAtment rescued mitochondriAl dysfunction induced by oligomeric Aβ42, including Adenosine triphosphAte (ATP) reduction, reActive oxygen species (ROS) overproduction And membrAne potentiAl depolArizAtion. Further study demonstrAted thAt Huperzine A Also significAntly reduced the level of Aβ42 in the mitochondriA-enriched subcellulAr frActions, As well As the Aβ42 fluorescent signAls colocAlized with mitochondriAl mArker. This study indicAtes thAt interfering intrAcellulAr Aβ especiAlly mitochondriAl Aβ AccumulAtion, together with AmeliorAting Aβ-AssociAted mitochondriAl dysfunction, mAy contribute to the protective effects of Huperzine A AgAinst Aβ neurotoxicity. Above results mAy shed more light on the phArmAcologicAl mechAnisms of Huperzine A And provide importAnt clues for discovering novel therApeutic strAtegies for AD.
-
QuAntitAtive proteomic AnAlysis reveAls the neuroprotective effects of Huperzine A for Amyloid betA treAted neuroblAstomA N2A cells
PROTEOMICS, 2013Co-Authors: Yimin Tao, Hualiang Jiang, Haiyan Zhang, Huaiyu Yang, Li Fang, Yiming Yang, Hu ZhouAbstract:Alzheimer's diseAse is A worldwide metAbolic diseAse And An economicAlly costly diseAse to society, so more medicines need to be developed to treAt this diseAse. Huperzine A, A novel lycopodium AlkAloid isolAted from trAditionAl Chinese medicine HuperziA serrAtA (QiAn Ceng TA), hAs been shown to possess multiple neuroprotective effects for Alzheimer's diseAse, but the precise phArmAcologicAl mechAnism of Huperzine A is uncleAr And needs to be further investigAted. In this study, proteins from untreAted N2A cells (Con group), cells preincubAted with Huperzine A followed by Aβ (1–42) oligomers treAtment (HupA group) And cells treAted with Aβ (1–42) oligomers (Aβ group) with five biologicAl replicAtes in eAch cohort, were processed in A centrifugAl proteomic reActor And quAntified by lAbel-free quAntitAtion. A totAl of 2860 proteins were quAntified with high confidence, And 198 proteins were significAntly chAnged (with p-vAlue < 0.05) between HupA And Aβ cohorts. The pAthwAy And direct protein–protein interAction network AnAlysis showed thAt Huperzine A protects N2A cells AgAinst Aβ oligomer-induced cell deAth by downregulAtion of cellulAr tumor Antigen p53 (Trp53) expression.
-
Free energy lAndscApe for the binding process of Huperzine A to AcetylcholinesterAse
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Yechun Xu, Jianpeng Ma, Jose N Onuchic, Junfeng Gu, Honglin Li, Jing Chen, Hualiang JiangAbstract:Drug-tArget residence time (t = 1/koff, where koff is the dissociAtion rAte constAnt) hAs become An importAnt index in discovering better- or best-in-clAss drugs. However, little effort hAs been dedicAted to developing computAtionAl methods thAt cAn AccurAtely predict this kinetic pArAmeter or relAted pArAmeters, koff And ActivAtion free energy of dissociAtion (). In this pAper, energy lAndscApe theory thAt hAs been developed to understAnd protein folding And function is extended to develop A generAlly ApplicAble computAtionAl frAmework thAt is Able to construct A complete ligAnd-tArget binding free energy lAndscApe. This enAbles both the binding Affinity And the binding kinetics to be AccurAtely estimAted. We Applied this method to simulAte the binding event of the Anti-Alzheimer’s diseAse drug (−)−Huperzine A to its tArget AcetylcholinesterAse (AChE). The computAtionAl results Are in excellent Agreement with our concurrent experimentAl meAsurements. All of the predicted vAlues of binding free energy And ActivAtion free energies of AssociAtion And dissociAtion deviAte from the experimentAl dAtA only by less thAn 1 kcAl/mol. The method Also provides Atomic resolution informAtion for the (−)−Huperzine A binding pAthwAy, which mAy be useful in designing more potent AChE inhibitors. We expect this methodology to be widely ApplicAble to drug discovery And development.
-
x rAy structures of torpedo cAlifornicA AcetylcholinesterAse complexed with Huperzine A And Huperzine b structurAl evidence for An Active site reArrAngement
Biochemistry, 2002Co-Authors: Hay Dvir, Hualiang Jiang, Israel Silman, D M Wong, M Harel, M Chetrit, X C He, G L Yu, X C Tang, Joel L. SussmanAbstract:Kinetic And structurAl dAtA Are presented on the interAction with Torpedo cAlifornicA AcetylcholinesterAse (TcAChE) of (+)-Huperzine A, A synthetic enAntiomer of the Anti-Alzheimer drug, (−)-Huperzine A, And of its nAturAl homologue (−)-Huperzine B. (+)-Huperzine A And (−)-Huperzine B bind to the enzyme with dissociAtion constAnts of 4.30 And 0.33 μM, respectively, compAred to 0.18 μM for (−)-Huperzine A. The X-rAy structures of the complexes of (+)-Huperzine A And (−)-Huperzine B with TcAChE were determined to 2.1 And 2.35 A resolution, respectively, And compAred to the previously determined structure of the (−)-Huperzine A complex. All three interAct with the “Anionic” subsite of the Active site, primArily through π−π stAcking And through vAn der WAAls or C−H···π interActions with Trp84 And Phe330. Since their α-pyridone moieties Are responsible for their key interActions with the Active site viA hydrogen bonding, And possibly viA C−H···π interActions, All three mAintAin similAr positions And orientAtio...
-
x rAy structures of torpedo cAlifornicA AcetylcholinesterAse complexed with Huperzine A And Huperzine b structurAl evidence for An Active site reArrAngement
Biochemistry, 2002Co-Authors: Hay Dvir, Hualiang Jiang, Israel Silman, D M Wong, M Harel, M Chetrit, X C Tang, G Y Jin, D L Bai, Joel L. SussmanAbstract:Kinetic And structurAl dAtA Are presented on the interAction with Torpedo cAlifornicA AcetylcholinesterAse (TcAChE) of (+)-Huperzine A, A synthetic enAntiomer of the Anti-Alzheimer drug, (-)-Huperzine A, And of its nAturAl homologue (-)-Huperzine B. (+)-Huperzine A And (-)-Huperzine B bind to the enzyme with dissociAtion constAnts of 4.30 And 0.33 microM, respectively, compAred to 0.18 microM for (-)-Huperzine A. The X-rAy structures of the complexes of (+)-Huperzine A And (-)-Huperzine B with TcAChE were determined to 2.1 And 2.35 A resolution, respectively, And compAred to the previously determined structure of the (-)-Huperzine A complex. All three interAct with the "Anionic" subsite of the Active site, primArily through pi-pi stAcking And through vAn der WAAls or C-H.pi interActions with Trp84 And Phe330. Since their AlphA-pyridone moieties Are responsible for their key interActions with the Active site viA hydrogen bonding, And possibly viA C-H.pi interActions, All three mAintAin similAr positions And orientAtions with respect to it. The cArbonyl oxygens of All three AppeAr to repel the cArbonyl oxygen of Gly117, thus cAusing the peptide bond between Gly117 And Gly118 to undergo A peptide flip. As A consequence, the position of the mAin chAin nitrogen of Gly118 in the "oxyAnion" hole in the nAtive enzyme becomes occupied by the cArbonyl of Gly117. Furthermore, the flipped conformAtion is stAbilized by hydrogen bonding of Gly117O to Gly119N And AlA201N, the other two functionAl elements of the three-pronged "oxyAnion hole" chArActeristic of cholinesterAses. All three inhibitors thus would be expected to Abolish hydrolysis of All ester substrAtes, whether chArged or neutrAl.
David R Gang - One of the best experts on this subject based on the ideXlab platform.
-
production of Huperzine A And other lycopodium AlkAloids in huperziA species grown under controlled conditions And in vitro
Phytochemistry, 2013Co-Authors: Kanichiro Ishiuchi, Jeongjin Park, Robert M Long, David R GangAbstract:A UPLC–MS method wAs developed for quAntifying Huperzine A (HupA), An Anti-Alzheimer’s diseAse (AD) drug cAndidAte from the trAditionAl Chinese medicine QiAn Ceng TA (HuperziA serrAtA), in sAmples of 11 HuperziA genus plAnts. The highest content of HupA wAs found in HuperziA pinifoliA. The AccumulAtion of vArious Lycopodium AlkAloids wAs monitored in these tissues using high resolution Q-IMS-TOFMS AnAlysis. Tissue culture of vArious HuperziA species hAs been Achieved And production of HupA hAs been confirmed in the cAllus of H. pinifoliA. Furthermore, it wAs estAblished thAt the mAjor AlkAloid produced by the nAturAlly grown plAnt And the cAllus of H. pinifoliA chAnged drAmAticAlly from HupA to nAnkAkurine B.
-
Huperzine A from huperziA species An ethnophArmAcolgicAl review
Journal of Ethnopharmacology, 2007Co-Authors: Changheng Tan, Dayuan Zhu, David R Gang, Peigen XiaoAbstract:Huperzine A (HupA), isolAted originAlly from A trAditionAl Chinese medicine QiAng Ceng TA, whole plAnt of HuperziA serrAtA (Thunb. ex MurrAy) Trev., A member of the HuperziAceAe fAmily, hAs AttrActed intense Attention since its mArked AnticholinesterAse Activity wAs discovered by Chinese scientists. SeverAl members of the HuperziAceAe (HuperziA And PhlegmAriurus species) hAve been used As medicines in ChinA for contusions, strAins, swellings, schizophreniA, myAstheniA grAvis And orgAnophosphAte poisoning. HupA hAs been mArketed in ChinA As A new drug for Alzheimer's diseAse (AD) treAtment And its derivAtive ZT-1 is being developed As Anti-AD new drug cAndidAte both in ChinA And in Europe. A review of the chemistry, bioActivities, toxicology, clinicAl triAls And nAturAl resources of HupA source plAnts is presented.
-
A survey of potentiAl Huperzine A nAturAl resources in chinA the huperziAceAe
Journal of Ethnopharmacology, 2006Co-Authors: Changheng Tan, Dayuan Zhu, David R GangAbstract:The HuperziAceAe is comprised of two generA, HuperziA And PhlegmAriurus. BecAuse of the content of Lycopodium AlkAloids like Huperzine A, which Are used to treAt A number of humAn Ailments, plAnts of the HuperziAceAe Are experiencing A rApid decline in ChinA, mostly due to over-hArvesting. BecAuse of this trend, we engAged from 1995 to 2001 in An investigAtion of the nAturAl resources of the HuperziAceAe in ChinA. The mAin objectives of this study were: to cAtAlog HuperziAceAe plAnt resources including the occurrence, generAl distribution, And AbundAnce of the vArious HuperziAceAe species in ChinA; And to determine trAditionAl use And phArmAceuticAl vAlues of eAch species. Twenty-nine species, 2 vArieties, And 2 formA of HuperziA And 19 species of PhlegmAriurus were identified through field investigAtion, collection, visits with locAl trAditionAl doctors, And review of specimens in herbAriA And of the literAture. EthnobotAnicAl studies of these plAnts reveAled thAt 33 of these species Are used by the locAl communities for medicinAl purposes. One species, HuperziA serrAtA, is one of the most populAr. As A result, it is observing the greAtest decline, mAndAting A chAnge in collection prActice And generAl Attitude towArds these plAnts. Introduction of conservAtion plAns And trAining of the locAl communities regArding AppropriAte collection prActices of these plAnts And their mArketing in ChinA Are required to reverse the trend of decline Among these species. In Addition, development of cultivAtion or other propAgAtion prActices, such As in vitro propAgAtion, would hAve the Added benefits of socio-economic uplift of the locAl communities And sustAinAbility of this importAnt source of Huperzine A.
-
is there A better source of Huperzine A thAn huperziA serrAtA Huperzine A content of huperziAceAe species in chinA
Journal of Agricultural and Food Chemistry, 2005Co-Authors: Changheng Tan, Dayuan Zhu, David R GangAbstract:A precise And selective reversed phAse high-performAnce liquid chromAtogrAphic method wAs developed for quAntifying Huperzine A (HupA) in sAmples of the HuperziAceAe in ChinA. This method wAs used to quAntify the levels of HupA in sAmples of HuperziA serrAtA collected from A single populAtion At different times of the yeAr, in different orgAns of the sAme H. serrAtA plAnt, And from different geogrAphicAl locAtions of H. serrAtA plAnts in ChinA. For different species of HuperziAceAe, the highest content of HupA wAs found in PhlegmAriurus cArinAtus. Members of the genus PhlegmAriurus possessed higher levels of HupA thAn HuperziA species. H. serrAtA plAnts growing in humid forests contAined significAntly more HupA thAn plAnts growing in less humid environments. FinAlly, HupA content vAried significAntly by seAson, with the highest levels being found in mid fAll And the lowest levels in eArly spring, suggesting thAt HupA is turned over in the plAnt.