The Experts below are selected from a list of 1128 Experts worldwide ranked by ideXlab platform
Gerhard Eisenbrand - One of the best experts on this subject based on the ideXlab platform.
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identification of a water soluble Indirubin derivative as potent inhibitor of insulin like growth factor 1 receptor through structural modification of the parent natural molecule
Journal of Medicinal Chemistry, 2017Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wolfl, Gerhard EisenbrandAbstract:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new Indirubin 3′- and 5′-derivatives in the search of water-soluble Indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position pr...
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Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
2017Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wölfl, Gerhard EisenbrandAbstract:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new Indirubin 3′- and 5′-derivatives in the search of water-soluble Indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble Indirubin-based IGF-1R inhibitor
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in vitro and in vivo evaluations of the performance of an Indirubin derivative formulated in four different self emulsifying drug delivery systems
Journal of Pharmacy and Pharmacology, 2014Co-Authors: Nasim Heshmati, Xinlai Cheng, Gerhard Eisenbrand, Else Dapat, Philip Jonas Sassene, Gert Fricker, Anette MullertzAbstract:Objectives Anticancer Indirubins are poorly soluble in water. Here, digestion of four self-emulsifying drug delivery systems (SEDDS) containing E804 (Indirubin-3′-oxime 2,3-dihydroxypropyl ether) was compared by dynamic lipolysis and bioavailability studies. Used lipids were either medium-chain or long-chain glycerides. Methods SEDDS E804 were developed. In-vitro lipolysis was carried out at pH 6.5 (37°C) by adding pancreatic lipase (800 U/ml) and controlling by CaCl2 and NaOH addition. E804 content was quantified in the aqueous micellar phase and precipitate using HPLC. Oral bioavailability was determined in rats. Plasma drug content was determined by liquid chromatography (LC)–mass spectrometry. Key findings All formulations reserved E804 in the aqueous micellar phase up to 60 min. Precipitation proceeded towards the end of lipolysis up to 45%. Lowest level of precipitation (21%) occurred with long-chain lipids (LC-SEDDS). However, lipolysis was not really discriminative between formulations as the drug mainly stayed in solution. Oral administration of formulations resulted in similar bioavailability of E804 with no significantly different area under the concentration curve. Only medium-chain self-nanoemulsifying drug delivery systems revealed shorter Tmax compared with the other formulations. Conclusion E804 had a similar performance in four lipid/surfactant systems. All formulations increased the bioavailability of E804 with no significant difference.
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7 7 diazaIndirubin a small molecule inhibitor of casein kinase 2 in vitro and in cells
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Christ, Stefan Wolfl, Gerhard EisenbrandAbstract:Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 μM, 7-azaIndirubin (12) and 7'-azaIndirubin (13) were more active than the parent molecule, Indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaIndirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for Indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 μM concentration, especially casein kinases CK1γ3, CK2α, CK2α2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells.
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Indirubin derivatives modulate tgfβ bmp signaling at different levels and trigger ubiquitin mediated depletion of nonactivated r smads
Chemistry & Biology, 2012Co-Authors: Xinlai Cheng, Karlheinz Merz, Gerhard Eisenbrand, Hamed Alborzinia, Herbert Steinbeisser, Ralf Mrowka, Catharina Scholl, Igor Kitanovic, Stefan WolflAbstract:Regulatory Smads (R-Smads), Smad1/5/8 and Smad2/3, are the central mediators of TGFβ and BMP signaling pathways. Here, we screened Indirubin derivatives, known kinase inhibitors, and observed strong interference with BMP signaling. We found that Indirubin derivative E738 inhibited both TGFβ and BMP pathways through ubiquitin-proteasome-mediated depletion of total R-Smad pools, although phospho-R-Smad levels were initially stabilized by GSK3β and cyclin-dependent kinase inhibition. E738 also enhanced p38 and JNK phosphorylation, involved in Smad-independent TGFβ/BMP signaling. Additionally, using a small siRNA screen, we showed that depletion of ubiquitin proteases USP9x and USP34 significantly reduced total R-Smad levels, mimicking E738 treatment. In fact, both USP9x and USP34 levels were significantly reduced in E738-treated cells. Our findings not only describe the complex activity profile of the Indirubin derivative E738, but also reveal a mechanism for controlling TGFβ/BMP signaling, the control of R-Smad protein levels through deubiquitination.
Shengquan Hu - One of the best experts on this subject based on the ideXlab platform.
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
Karl Wah Keung Tsim - One of the best experts on this subject based on the ideXlab platform.
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
Xinlai Cheng - One of the best experts on this subject based on the ideXlab platform.
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identification of a water soluble Indirubin derivative as potent inhibitor of insulin like growth factor 1 receptor through structural modification of the parent natural molecule
Journal of Medicinal Chemistry, 2017Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wolfl, Gerhard EisenbrandAbstract:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new Indirubin 3′- and 5′-derivatives in the search of water-soluble Indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position pr...
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Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
2017Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wölfl, Gerhard EisenbrandAbstract:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new Indirubin 3′- and 5′-derivatives in the search of water-soluble Indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble Indirubin-based IGF-1R inhibitor
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in vitro and in vivo evaluations of the performance of an Indirubin derivative formulated in four different self emulsifying drug delivery systems
Journal of Pharmacy and Pharmacology, 2014Co-Authors: Nasim Heshmati, Xinlai Cheng, Gerhard Eisenbrand, Else Dapat, Philip Jonas Sassene, Gert Fricker, Anette MullertzAbstract:Objectives Anticancer Indirubins are poorly soluble in water. Here, digestion of four self-emulsifying drug delivery systems (SEDDS) containing E804 (Indirubin-3′-oxime 2,3-dihydroxypropyl ether) was compared by dynamic lipolysis and bioavailability studies. Used lipids were either medium-chain or long-chain glycerides. Methods SEDDS E804 were developed. In-vitro lipolysis was carried out at pH 6.5 (37°C) by adding pancreatic lipase (800 U/ml) and controlling by CaCl2 and NaOH addition. E804 content was quantified in the aqueous micellar phase and precipitate using HPLC. Oral bioavailability was determined in rats. Plasma drug content was determined by liquid chromatography (LC)–mass spectrometry. Key findings All formulations reserved E804 in the aqueous micellar phase up to 60 min. Precipitation proceeded towards the end of lipolysis up to 45%. Lowest level of precipitation (21%) occurred with long-chain lipids (LC-SEDDS). However, lipolysis was not really discriminative between formulations as the drug mainly stayed in solution. Oral administration of formulations resulted in similar bioavailability of E804 with no significantly different area under the concentration curve. Only medium-chain self-nanoemulsifying drug delivery systems revealed shorter Tmax compared with the other formulations. Conclusion E804 had a similar performance in four lipid/surfactant systems. All formulations increased the bioavailability of E804 with no significant difference.
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7 7 diazaIndirubin a small molecule inhibitor of casein kinase 2 in vitro and in cells
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Xinlai Cheng, Sandra Vatter, Karlheinz Merz, Jochen Christ, Stefan Wolfl, Gerhard EisenbrandAbstract:Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 μM, 7-azaIndirubin (12) and 7'-azaIndirubin (13) were more active than the parent molecule, Indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaIndirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for Indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 μM concentration, especially casein kinases CK1γ3, CK2α, CK2α2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells.
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Indirubin derivatives modulate tgfβ bmp signaling at different levels and trigger ubiquitin mediated depletion of nonactivated r smads
Chemistry & Biology, 2012Co-Authors: Xinlai Cheng, Karlheinz Merz, Gerhard Eisenbrand, Hamed Alborzinia, Herbert Steinbeisser, Ralf Mrowka, Catharina Scholl, Igor Kitanovic, Stefan WolflAbstract:Regulatory Smads (R-Smads), Smad1/5/8 and Smad2/3, are the central mediators of TGFβ and BMP signaling pathways. Here, we screened Indirubin derivatives, known kinase inhibitors, and observed strong interference with BMP signaling. We found that Indirubin derivative E738 inhibited both TGFβ and BMP pathways through ubiquitin-proteasome-mediated depletion of total R-Smad pools, although phospho-R-Smad levels were initially stabilized by GSK3β and cyclin-dependent kinase inhibition. E738 also enhanced p38 and JNK phosphorylation, involved in Smad-independent TGFβ/BMP signaling. Additionally, using a small siRNA screen, we showed that depletion of ubiquitin proteases USP9x and USP34 significantly reduced total R-Smad levels, mimicking E738 treatment. In fact, both USP9x and USP34 levels were significantly reduced in E738-treated cells. Our findings not only describe the complex activity profile of the Indirubin derivative E738, but also reveal a mechanism for controlling TGFβ/BMP signaling, the control of R-Smad protein levels through deubiquitination.
Zaijun Zhang - One of the best experts on this subject based on the ideXlab platform.
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Indirubin 3 oxime prevents h2o2 induced neuronal apoptosis via concurrently inhibiting gsk3β and the erk pathway
Cellular and Molecular Neurobiology, 2017Co-Authors: Jiacheng Zheng, Zaijun Zhang, Jiajia Lin, Linlu Jin, Shinghung Mak, Hongya Sun, Mingyuen Lee, Wahkeung Tsim, Wenhua Zhou, Wei CuiAbstract:Oxidative stress-induced neuronal apoptosis plays an important role in many neurodegenerative disorders. In this study, we have shown that Indirubin-3-oxime, a derivative of Indirubin originally designed for leukemia therapy, could prevent hydrogen peroxide (H2O2)-induced apoptosis in both SH-SY5Y cells and primary cerebellar granule neurons. H2O2 exposure led to the increased activities of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) in SH-SY5Y cells. Indirubin-3-oxime treatment significantly reversed the altered activity of both the PI3-K/Akt/GSK3β cascade and the ERK pathway induced by H2O2. In addition, both GSK3β and mitogen-activated protein kinase inhibitors significantly prevented H2O2-induced neuronal apoptosis. Moreover, specific inhibitors of the phosphoinositide 3-kinase (PI3-K) abolished the neuroprotective effects of Indirubin-3-oxime against H2O2-induced neuronal apoptosis. These results strongly suggest that Indirubin-3-oxime prevents H2O2-induced apoptosis via concurrent inhibiting GSK3β and the ERK pathway in SH-SY5Y cells, providing support for the use of Indirubin-3-oxime to treat neurodegenerative disorders caused or exacerbated by oxidative stress.
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Indirubin Derivative 7-BromoIndirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice
Frontiers Media S.A., 2017Co-Authors: Liping Chen, Chunhui Huang, Jieyi Shentu, Minjun Wang, Sicheng Yan, Fei Zhou, Zaijun ZhangAbstract:Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoIndirubin-3-oxime (7Bio), an Indirubin derivative derived from Indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3–23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
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Indirubin 3 oxime effectively prevents 6ohda induced neurotoxicity in pc12 cells via activating mef2d through the inhibition of gsk3β
Journal of Molecular Neuroscience, 2015Co-Authors: Shengquan Hu, Daping Xu, Yuanjia Hu, Zaijun Zhang, Yuqiang Wang, Gang Li, Karl Wah Keung TsimAbstract:Indirubin-3-oxime (I3O), a synthetic derivative of Indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, Indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of Indirubin-3-oxime. Collectively, our results strongly suggested that Indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of Indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that Indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.
