Wenming Li

Diabetes mellitus is a chronic metabolic disease with a proinflammatory microenvironment, causing poor vascularization and bone regeneration. Due to the lack of effective therapy and one-sided focus on the direct angiogenic properties of biomaterials and osteogenesis stimulation, the treatment of diabetic bone defect remains challenging and complex. In this study, using gelatin methacryloyl (GelMA) as a template, a lithium (Li) -modified bioglass-hydrogel for diabetic bone regeneration is developed. It exhibits a sustained ion release for better bone regeneration under diabetic microenvironment. The hydrogel is shown to be mechanically adaptable to the complex shape of the defect. In vitro, Li-modified bioglass-hydrogel promoted cell proliferation, direct osteogenesis, and regulated macrophages in high glucose (HG) microenvironment, with the secretion of bone morphogenetic protein-2 and vascular endothelial growth factor to stimulate osteogenesis and neovascularization indirectly. In vivo, composite hydrogels containing GelMA and Li-MBG (GM/M-Li) release Li ions to relieve inflammation, providing an anti-inflammatory microenvironment for osteogenesis and angiogenesis. Applying Li-modified bioglass-hydrogel, significantly enhances bone regeneration in a diabetic rat bone defect. Together, both remarkable in vitro and in vivo outcomes in this study present an opportunity for diabetic bone regeneration on the basis of HG microenvironment.

BACKGROUND: The identification of gastric superficial cancerous lesions based on conventional white-light endoscopy (WLE) is challenging, and histological analysis remains the 'gold standard' for the final diagnosis. Confocal laser endomicroscopy (CLE) can provide in vivo histological observation without the need for biopsy. OBJECTIVE: To develop and evaluate CLE imaging criteria for gastric superficial cancerous lesions and to compare the diagnostic value of real-time integrated CLE (iCLE) and WLE alone in distinguishing gastric superficial cancerous lesions. DESIGN: Prospective study. SETTING: Qilu Hospital, Shandong University, Jinan, China. PATIENTS: A total of 182 patients were enrolled into phase I and 1786 patients were enrolled into phase II. INTERVENTIONS: CLE images were blindly evaluated after endoscopy in phase I, and real-time iCLE diagnosis during endoscopy was compared with WLE diagnosis by using histopathology as a gold standard in phase II. MAIN OUTCOME MEASUREMENTS: The validity and reliability of the CLE diagnosis for identifying gastric superficial cancerous lesions. RESULTS: Off-line CLE diagnosis for early gastric cancers had a high sensitivity (88.1%) and specificity (98.6%). When the two-tiered CLE classification of non-cancerous lesions and cancer/high-grade intraepithelial neoplasia (HGIN) lesions was introduced, CLE diagnosis led to a higher sensitivity (90.2%) and specificity (98.5%) (phase I). Real-time iCLE diagnosis had a higher sensitivity (88.9%), specificity (99.3%) and accuracy (98.8%) for gastric superficial cancer/HGIN lesions than WLE diagnosis (sensitivity, 72.2%; specificity, 95.1%; and accuracy, 94.1%) (p < 0.05) (phase II). Limitations This was a single-centre study. CONCLUSIONS: CLE can be used to identify gastric superficial cancer/HGIN lesions with high validity and reliability.

The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 μm glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment (0.01–1 μm) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 μm bis(7)-tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-β-erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-tacrine, suggesting that the neuroprotection of bis(7)-tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-d-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca2+ imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-tacrine was found effectively to buffer the intracellular Ca2+ increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [3H]MK-801 with an IC50 value of 0.763 μm in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects. The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 μm glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment (0.01–1 μm) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 μm bis(7)-tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-β-erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-tacrine, suggesting that the neuroprotection of bis(7)-tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-d-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca2+ imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-tacrine was found effectively to buffer the intracellular Ca2+ increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [3H]MK-801 with an IC50 value of 0.763 μm in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects. Bis(7)-tacrine (1,7-N-heptylene-bis-9,9′-amino-1,2,3,4-tetrahydroacridine), a novel dimeric AChE 1The abbreviations used are: AChE, acetylcholinesterase; AD, Alzheimer disease; CGN, cerebellar granule neuron; DIV, day(s) in vitro; E2020, donepezil; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; MKK, mitogen-activated protein kinase kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; NMDA, N-methyl-d-aspartate; FDA, fluorescein diacetate; ANOVA, analysis of variance; APV, 2-amino-5-phosphonovalerate; DNQX, 6,7-dinitroquinoxaline-2,3-dione; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione. 1The abbreviations used are: AChE, acetylcholinesterase; AD, Alzheimer disease; CGN, cerebellar granule neuron; DIV, day(s) in vitro; E2020, donepezil; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; MKK, mitogen-activated protein kinase kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; NMDA, N-methyl-d-aspartate; FDA, fluorescein diacetate; ANOVA, analysis of variance; APV, 2-amino-5-phosphonovalerate; DNQX, 6,7-dinitroquinoxaline-2,3-dione; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione. inhibitor derived from tacrine, has been reported by us as a promising palliative therapeutic agent for Alzheimer disease (AD) on the basis of its superior AChE inhibition (1Pang Y.P. Quiram P. Jelacic T. Hong F. Brimijoin S. J. Biol. Chem. 1996; 271: 23646-23649Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 2Wang H. Carlier P.R. Ho W.L. Wu D.C. Lee N.T. Li C.P. Pang Y.P. Han Y.F. Neuroreport. 1999; 10: 789-793Crossref PubMed Scopus (70) Google Scholar) and memory enhancement potency relative to tacrine (3Liu J. Ho W.L. Lee N.T. Carlier P.R. Pang Y.P. Han Y.F. Neurosci. Lett. 2000; 282: 165-168Crossref PubMed Scopus (48) Google Scholar). Moreover, bis(7)-tacine protects against ischemia-induced injury in primary cultured mouse astrocytes (4Wu D.C. Xiao X.Q. Ng A.K. Chen P.M. Chung W. Lee N.T. Carlier P.R. Pang Y.P. Yu A.C. Han Y.F. Neurosci. Lett. 2000; 288: 95-98Crossref PubMed Scopus (41) Google Scholar) and hydrogen peroxide-induced apoptosis in pheochromocytoma cells (5Xiao X.Q. Lee N.T. Carlier P.R. Pang Y. Han Y.F. Neurosci. Lett. 2000; 290: 197-200Crossref PubMed Scopus (65) Google Scholar). Although it has been shown that bis(7)-tacrine reverses memory deficits mainly via the inhibition on AChE, its exact multiple neuroprotective mechanisms remain elusive. AD is a multifaceted neurodegenerative disease characterized by the progressive deterioration of cognition and memory in association with widespread neuronal loss (6Villarroya M. Garcia A.G. Marco J.L. Curr. Pharm. Des. 2004; 10: 3177-3184Crossref PubMed Scopus (41) Google Scholar). The link between cholinergic dysfunction and AD severity provides a firm rationale for the therapeutic use of AChE inhibitors, such as tacrine, donepezil (E2020), rivastigmine, galanthamine, and huperizine A (7Weinstock M. Neurodegeneration. 1995; 4: 349-356Crossref PubMed Scopus (98) Google Scholar, 8Sugimoto H. Yamanishi Y. Iimura Y. Kawakami Y. Curr. Med. Chem. 2000; 7: 303-339Crossref PubMed Scopus (279) Google Scholar, 9Soreq H. Seidman S. Isr. Med. Assoc. J. 2000; 2: 81-85PubMed Google Scholar). 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Transm. 2000; 107: PubMed Scopus Google Scholar, X.Q. Zhang H.Y. Tang X.C. J. Neurosci. Res. PubMed Scopus Google Scholar). is an in neurodegenerative and in neuronal F. 1996; Google Scholar, Nature. 1999; PubMed Scopus Google Scholar). In these is an of glutamate that to the The glutamate an activation of glutamate receptors of the NMDA to an of Ca2+ in the neurons and a neuronal A. S. J. Neurosci. 2001; PubMed Google Scholar, J. 2004; PubMed Scopus Google Scholar, M. S. P. 1995; Full Text PDF PubMed Scopus Google Scholar). Several kinase pathways, mainly extracellular and p38 mitogen-activated protein kinase pathways, have been demonstrated to be in glutamate-induced apoptosis and to be for the downstream signals of intracellular Ca2+ Zhang Brain Res. 2000; PubMed Scopus Google Scholar, H. T. S. J. T. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The and of are in activated by a of receptors in and and activated in the and to the it a of W. 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However, the between and p38 in glutamate-induced apoptosis has not been The studies were to the of bis(7)-tacrine to prevent glutamate-induced apoptosis in CGNs and to agent the of glutamate-induced apoptosis from and p38 to intracellular Ca2+ to NMDA appears that bis(7)-tacrine prevents glutamate-induced apoptosis in neurons by directly blocking NMDA receptors at the MK-801-binding independent of the inhibition on AChE and cholinergic transmission. cerebellar granule neurons were from rat Hong of as Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). neurons were at a of in and μm) was to the after to the of the use of of the cultured cells were granule The were after in of of neurons in the of bis(7)-tacrine glutamate was by the of with Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). The was to the of the the neurons were cultured in of was to cells in of and the was at the of the in was to for The of the was at a of with as a the of in cells to glutamate is as a of the granule neurons were with fluorescein from FDA, which is only by cells Pharmacol. 1995; Google Scholar). after with for the neurons were and were using at with Hoechst was by with Hoechst as Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). CGNs in a were with phosphate-buffered and with in The cells were with Hoechst for at The were using a fluorescence at DNA fragmentation was using a DNA as Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). CGNs in a were in and The was at for The was with and A and in the of The DNA was with and in 1 The DNA was in in The DNA were by and were with to the of the neurons were with PBS, with for and with The cells were with in and with and with of buffer at for The DNA was using of of of and 1 of for at and the was by the in for at The were with and for a fluorescence using a fluorescein to the using a fluorescein at AChE was by using a H. Carlier P.R. Ho W.L. Wu D.C. Lee N.T. Li C.P. Pang Y.P. Han Y.F. Neuroreport. 1999; 10: 789-793Crossref PubMed Scopus (70) Google Scholar). the were from of CGNs after glutamate by at for at for the was with for to inhibit the using at as AChE and at as the at was by at at for protein concentrations were by the Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar), and the of AChE was by the from independent analysis was as Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). the neurons were by buffer and The were by with the use of as in the The were to The were with primary with the primary the were and with the the were and were with an and to kinase was using kinase by the kinase Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). In CGNs were with and in an the p38 kinase from CGNs with were with the p38 by to The were with a buffer and with a kinase The kinase was by of protein as the of p38 and μm and by buffer after for at In bis(7)-tacrine was to the of The were using with the was used to relative in intracellular concentrations by fluorescence after intracellular of with at and at Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). In the neurons were with for in a and with a The fluorescence were using the The were by the fluorescence from a of and by the fluorescence as were and Bis(7)-tacrine was to the to of neurons on were from for the patch analysis Y. S. Pharmacol. Google Scholar). were in and 1 in in at for in at and using a The neurons were on of in and 1 of was with a of 1 and was The neurons were cultured for to use in patch was at using an patch Y. S. Pharmacol. Google Scholar). was at The were at and on a using a and The neurons were at in an extracellular was to using and was to using Ca2+ was used to NMDA The was to using and was to using of and were in extracellular and were to neurons by from a of μm) to independent the were by the using a of the at an was binding was as T. S. A. PubMed Scopus Google Scholar) with was from the of by using as T. S. A. PubMed Scopus Google Scholar). The binding was in using of synaptic protein and [3H]MK-801 with concentrations of binding was by an of the the on by with a on was for and in a binding to receptors was by the from the which is by The are derived from the IC50 by for by The binding were with the of in and are as the and was by analysis of with in the of multiple with for multiple between treatment were by The were as significant at Bis(7)-tacrine in to the of bis(7)-tacrine on glutamate a dose- and time-dependent excitotoxicity in CGNs was in CGNs were to μm glutamate for 75 μm glutamate at was by a loss in neuronal from μm and at μm at 75 μm a time-dependent neuronal at and at CGNs were with the concentrations of bis(7)-tacrine for and to 75 μm glutamate for with 1 μm bis(7)-tacrine for and to concentrations of glutamate for was found that bis(7)-tacrine 75 μm glutamate-induced in CGNs in a Bis(7)-tacrine at 1 μm its neuroprotective for at after glutamate the increase of glutamate the neuroprotective properties of bis(7)-tacrine and were CGNs were to μm glutamate Bis(7)-tacrine in glutamate apoptosis on the and at glutamate more apoptosis not Y. 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The by Hoechst and demonstrated that 75 μm glutamate-induced apoptosis and bis(7)-tacrine prevent glutamate-induced apoptosis in DIV, CGNs were with 1 μm bis(7)-tacrine and to 75 μm glutamate and the and that bis(7)-tacrine the loss of neurons and the and by glutamate The Hoechst that bis(7)-tacrine whereas the that bis(7)-tacrine glutamate-induced increase in neurons The of by Hoechst that bis(7)-tacrine by by glutamate neuronal apoptosis by glutamate, a DNA fragmentation was on the CGNs The that bis(7)-tacrine the DNA fragmentation in CGNs by glutamate The of Bis(7)-tacrine of AChE and is a and inhibitor of AChE, and it is the neuroprotective properties of bis(7)-tacrine were by inhibiting AChE Therefore, bis(7)-tacrine, with two other AChE inhibitors and and AChE inhibitor was used to prevent glutamate-induced apoptosis in CGNs. it was shown that tacrine at and at μm failed to apoptosis in CGNs by 75 μm glutamate A and Although μm of and 1 μm of bis(7)-tacrine a similar on inhibiting the of AChE failed to the neuronal DNA and DNA by 75 μm glutamate in CGNs of cholinergic receptors is to prevent neuronal apoptosis Pharmacol. 1995; Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Bis(7)-tacrine the of AChE and the increase of concentrations of in in which may contribute to the therapeutic against AD H. Carlier P.R. Ho W.L. Wu D.C. Lee N.T. Li C.P. Pang Y.P. Han Y.F. Neuroreport. 1999; 10: 789-793Crossref PubMed Scopus (70) Google Scholar, J. Ho W.L. Lee N.T. Carlier P.R. Pang Y.P. Han Y.F. Neurosci. Lett. 2000; 282: 165-168Crossref PubMed Scopus (48) Google Scholar). the neuroprotective properties of bis(7)-tacrine was by of cholinergic receptors directly both atropine and cholinergic were the same cultured it was shown that μm μm dihydro-β-erythroidine, failed to the neuroprotective properties of 1 μm bis(7)-tacrine against 75 μm glutamate-induced apoptosis in CGNs Bis(7)-tacrine the of and p38 by and p38 are with apoptosis in neurons Zhang Brain Res. 2000; PubMed Scopus Google Scholar, H. T. S. J. T. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and p38 are in glutamate-induced apoptosis in cultured the inhibitors of and the inhibitors of p38 were to the CGNs for was that glutamate-induced apoptosis in a The of at 1 μm and at μm a neuroprotective and the of at μm at μm inhibition on glutamate-induced apoptosis bis(7)-tacrine neurons through inhibition of the of and were by shown in glutamate at 75 μm the increase of and bis(7)-tacrine inhibited in a time-dependent the other glutamate the of and in a time-dependent which at and to at and after glutamate not Bis(7)-tacrine inhibited the of these by glutamate at whereas only inhibited the in bis(7)-tacrine glutamate-induced apoptosis by inhibition of p38 the of and the of p38 kinase were by was found that 75 μm glutamate the increase of and in a time-dependent and 1 μm bis(7)-tacrine the increase of and by glutamate the kinase both in and in as it was demonstrated that bis(7)-tacrine inhibited the activation of p38 by 75 μm glutamate in a in did not directly inhibit the of in using as a Bis(7)-tacrine the of to the bis(7)-tacrine inhibit the activation of and p38 by glutamate, that bis(7)-tacrine may inhibit the of and p38 the of intracellular Ca2+ in and the intracellular Ca2+ at concentrations is to and p38 Zhang Brain Res. 2000; PubMed Scopus Google Scholar, H. T. S. J. T. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). bis(7)-tacrine with intracellular fluorescence was used for the Ca2+ in CGNs. be that 75 μm glutamate a intracellular Ca2+ increase A and In treatment the neurons were with a 1 μm 1 μm bis(7)-tacrine for and to 75 μm The intracellular Ca2+ was these with which the in intracellular Ca2+ by glutamate, bis(7)-tacrine inhibited the intracellular Ca2+ triggered by glutamate was significant in both and of the intracellular Ca2+ the of between the neurons with the and bis(7)-tacrine Bis(7)-tacrine NMDA at the MK-801-binding bis(7)-tacrine reduced intracellular Ca2+ by directly NMDA receptors, that apoptosis was by at 1 μm of NMDA at μm of NMDA not by the and at μm at μm that glutamate-induced was mainly by the of NMDA receptors Zhang Brain Res. 2000; PubMed Scopus Google Scholar, H. T. S. J. T. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the between bis(7)-tacrine and NMDA receptors, patch were in primary cultured NMDA currents were using the of μm NMDA currents were at the the an and to a of of the The from neurons that in the of bis(7)-tacrine and 1 tacrine μm) μm currents were and of the value that bis(7)-tacrine, not tacrine and E2020, reduced the by Furthermore, to receptor-ligand binding with bis(7)-tacrine with [3H]MK-801 with an IC50 of 0.763 whereas tacrine μm) and μm) only with [3H]MK-801 in rat cerebellar AChE inhibitors, such as tacrine and have been shown to the apoptosis of neurons by (10Wang R. Zhang H.Y. Tang X.C. Eur. J. Pharmacol. 2001; 421: 149-156Crossref PubMed Scopus (125) Google Scholar, R. J. Tang X.C. Brain Res. Brain Res. 107: PubMed Scopus Google Scholar). Bis(7)-tacrine is to prevent neuronal apoptosis and injury (4Wu D.C. Xiao X.Q. Ng A.K. Chen P.M. Chung W. Lee N.T. Carlier P.R. Pang Y.P. Yu A.C. Han Y.F. Neurosci. Lett. 2000; 288: 95-98Crossref PubMed Scopus (41) Google Scholar, X.Q. Lee N.T. Carlier P.R. Pang Y. Han Y.F. Neurosci. Lett. 2000; 290: 197-200Crossref PubMed Scopus (65) Google Scholar). However, the exact mechanisms of its neuroprotective remain elusive. In the that glutamate at concentrations apoptosis was in as demonstrated by Li Lee D.C. Li Han Y.F. J. 2004; PubMed Scopus Google Scholar). using have investigated the neuroprotective and the mechanisms of was found that bis(7)-tacrine inhibited the glutamate-induced apoptosis in a and its was significant even at μm bis(7)-tacrine is a and AChE inhibitor (1Pang Y.P. Quiram P. Jelacic T. Hong F. Brimijoin S. J. Biol. Chem. 1996; 271: 23646-23649Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 2Wang H. Carlier P.R. Ho W.L. Wu D.C. Lee N.T. Li C.P. Pang Y.P. Han Y.F. 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However, the between and p38 in the apoptosis by glutamate is as In have found that at both inhibitors and p38 inhibitors prevent the by glutamate The the findings that and p38 may be in glutamate-induced apoptosis in the of and the that these two kinase might a role in glutamate-induced it has been found that bis(7)-tacrine the activation of and p38 by to the in bis(7)-tacrine the of and inhibition of in the that bis(7)-tacrine the of the than directly the other bis(7)-tacrine the activation of and p38 by glutamate in CGNs not directly inhibit the of in which that bis(7)-tacrine the p38 by with the of the bis(7)-tacrine glutamate-induced apoptosis via the inhibition of the of and p38 pathways, which may bis(7)-tacrine more neuroprotective than the inhibitors of the inhibitors of p38 has reported that the of intracellular Ca2+ both and p38 Zhang Brain Res. 2000; PubMed Scopus Google Scholar, H. T. S. J. T. Y. J. Biol. Chem. 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Parsons C.G. Int. J. Geriatr. Psychiatry. 2003; 18: S23-S32Crossref PubMed Scopus (307) Google Scholar, Neurosci. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In that bis(7)-tacrine apoptosis in neurons through the of NMDA receptors at the MK-801-binding appears to be independent of inhibiting AChE and cholinergic transmission. Moreover, glutamate neuronal apoptosis by both the and p38 that a role in the downstream signals of intracellular Bis(7)-tacrine the of intracellular Ca2+ by glutamate through blocking NMDA receptors and two and p38 and these and (1Pang Y.P. Quiram P. Jelacic T. Hong F. Brimijoin S. J. Biol. Chem. 1996; 271: 23646-23649Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 2Wang H. Carlier P.R. Ho W.L. Wu D.C. Lee N.T. Li C.P. Pang Y.P. Han Y.F. Neuroreport. 1999; 10: 789-793Crossref PubMed Scopus (70) Google Scholar, J. Ho W.L. Lee N.T. Carlier P.R. Pang Y.P. Han Y.F. Neurosci. 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