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Article ; Online: Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer's disease models.

Guan, Xin-Jie / Deng, Zhi-Qiang / Liu, Jia / Su, Cheng-Fu / Tong, Benjamin Chun-Kit / Zhu, Zhou / Sreenivasmurthy, Sravan Gopalkrishnashetty / Kan, Yu-Xuan / Lu, Ke-Jia / Chu, Carol Pui-Kei / Pi, Rong-Biao / Cheung, King-Ho / Iyaswamy, Ashok / Song, Ju-Xian / Li, Min

Acta pharmacologica Sinica

2024 Volume 45, Issue 5, Page(s) 900–913

Abstract: Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. ... ...

Abstract	Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in AD models.
MeSH term(s)	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Animals ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Autophagy/drug effects ; Mice ; Disease Models, Animal ; Lysosomes/metabolism ; Lysosomes/drug effects ; Humans ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; TOR Serine-Threonine Kinases/metabolism ; Male ; Proto-Oncogene Proteins c-akt/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Signal Transduction/drug effects ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Protein Precursor/genetics ; Transient Receptor Potential Channels
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Tcfeb protein, mouse ; Tcfe3 protein, mouse (136896-33-8) ; Mcoln1 protein, mouse ; Amyloid beta-Peptides ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Amyloid beta-Protein Precursor ; Transient Receptor Potential Channels
Language	English
Publishing date	2024-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-023-01197-1
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Article ; Online: Calcium signaling in Alzheimer's disease & therapies.

Tong, Benjamin Chun-Kit / Wu, Aston Jiaxi / Li, Min / Cheung, King-Ho

Biochimica et biophysica acta. Molecular cell research

2018 Volume 1865, Issue 11 Pt B, Page(s) 1745–1760

Abstract: Alzheimer's disease (AD) is the most common type of dementia and is characterized by the accumulation of amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Much attention has been given to develop AD treatments based on the amyloid cascade ... ...

Abstract	Alzheimer's disease (AD) is the most common type of dementia and is characterized by the accumulation of amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Much attention has been given to develop AD treatments based on the amyloid cascade hypothesis; however, none of these drugs had good efficacy at improving cognitive functions in AD patients suggesting that Aβ might not be the disease origin. Thus, there are urgent needs for the development of new therapies that target on the proximal cause of AD. Cellular calcium (Ca
MeSH term(s)	Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/therapy ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Disease Susceptibility ; Homeostasis ; Humans ; Molecular Targeted Therapy ; Neurons/metabolism ; Phosphorylation ; Protein Aggregation, Pathological ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; tau Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-07-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2018.07.018
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Article ; Online: Targeting calcium signaling by inositol trisphosphate receptors: A novel mechanism for the anti-asthmatic effects of Houttuynia cordata.

Huang, Alexis Shiying / Tong, Benjamin Chun-Kit / Hung, Harry Chun-Hin / Wu, Aston Jiaxi / Ho, Olivia Ka-Yi / Kong, Anna Hau-Yee / Leung, Maggie Ming-Ki / Bai, Jingxuan / Fu, Xiuqiong / Yu, Zhiling / Li, Min / Leung, Ting Fan / Mak, Judith Choi-Wo / Leung, George Pak-Heng / Cheung, King-Ho

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 164, Page(s) 114935

Abstract: Asthma is a chronic inflammatory disease characterized by airway hypersensitivity and remodeling. The current treatments provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because ...

Abstract	Asthma is a chronic inflammatory disease characterized by airway hypersensitivity and remodeling. The current treatments provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because intracellular calcium (Ca
MeSH term(s)	Humans ; Calcium Signaling ; Houttuynia/metabolism ; Anti-Asthmatic Agents/pharmacology ; Anti-Asthmatic Agents/therapeutic use ; Bronchi/metabolism ; Asthma/drug therapy ; Inositol 1,4,5-Trisphosphate Receptors/metabolism ; Calcium/metabolism
Chemical Substances	decanoyl acetaldehyde (56505-80-7) ; Anti-Asthmatic Agents ; Inositol 1,4,5-Trisphosphate Receptors ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2023-05-26
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.114935
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Article ; Online: Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies.

Tong, Benjamin Chun-Kit / Huang, Alexis Shiying / Wu, Aston Jiaxi / Iyaswamy, Ashok / Ho, Olivia Ka-Yi / Kong, Anna Hau-Yee / Sreenivasmurthy, Sravan Gopalkrishnashetty / Zhu, Zhou / Su, Chengfu / Liu, Jia / Song, Juxian / Li, Min / Cheung, King-Ho

Journal of biomedical science

2022 Volume 29, Issue 1, Page(s) 85

Abstract: Background: Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer's disease (AD) ... ...

Abstract	Background: Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. Methods: Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca Results: We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca Conclusions: Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca
MeSH term(s)	Animals ; Mice ; tau Proteins/genetics ; Calcium ; Disease Models, Animal ; Tauopathies/drug therapy ; Tauopathies/pathology ; Mice, Transgenic ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Cognition
Chemical Substances	tetrandrine (29EX23D5AJ) ; tau Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-10-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-022-00871-6
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Article ; Online: Correction to: InsP

Yang, Long / Gu, Wenwen / Cheung, King-Ho / Yan, Lan / Tong, Benjamin Chun-Kit / Jiang, Yuanying / Yang, Jun

BMC biology

2020 Volume 18, Issue 1, Page(s) 158

Abstract: An amendment to this paper has been published and can be accessed via the original article. ...

Abstract	An amendment to this paper has been published and can be accessed via the original article.
Language	English
Publishing date	2020-11-02
Publishing country	England
Document type	Published Erratum
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/s12915-020-00900-6
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Article ; Online: Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models.

Iyaswamy, Ashok / Wang, Xueli / Krishnamoorthi, Senthilkumar / Kaliamoorthy, Venkatapathy / Sreenivasmurthy, Sravan G / Kumar Durairajan, Siva Sundara / Song, Ju-Xian / Tong, Benjamin Chun-Kit / Zhu, Zhou / Su, Cheng-Fu / Liu, Jia / Cheung, King-Ho / Lu, Jia-Hong / Tan, Jie-Qiong / Li, Hung Wing / Wong, Man Shing / Li, Min

Redox biology

2022 Volume 51, Page(s) 102280

Abstract: Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to ... ...

Abstract	Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aβ-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aβ aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aβ oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aβ, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Cognition ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Theranostic Nanomedicine ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; tau Proteins
Language	English
Publishing date	2022-03-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2022.102280
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Article ; Online: InsP

Yang, Long / Gu, Wenwen / Cheung, King-Ho / Yan, Lan / Tong, Benjamin Chun-Kit / Jiang, Yuanying / Yang, Jun

BMC biology

2018 Volume 16, Issue 1, Page(s) 46

Abstract: Background: Candida albicans (C. albicans) invasion triggers antifungal innate immunity, and the elevation of cytoplasmic Ca: Results: In the present study, we find that during C. albicans phagocytosis in macrophages, exocyst complex component 2 ( ... ...

Abstract	Background: Candida albicans (C. albicans) invasion triggers antifungal innate immunity, and the elevation of cytoplasmic Ca Results: In the present study, we find that during C. albicans phagocytosis in macrophages, exocyst complex component 2 (SEC5) promotes InsP Conclusions: Our data have revealed an important role of the InsP
MeSH term(s)	Animals ; Calcium/metabolism ; Candida albicans/metabolism ; Cytoplasm/metabolism ; Cytosol/metabolism ; HEK293 Cells ; Humans ; Immunity, Innate/physiology ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/metabolism ; Mice ; Phagocytosis/physiology ; Phagosomes/metabolism ; Vesicular Transport Proteins/metabolism
Chemical Substances	Exoc2 protein, mouse ; Interferon Regulatory Factor-3 ; Interferon Type I ; Vesicular Transport Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-04-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/s12915-018-0507-6
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Article: Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition

Sreenivasmurthy, Sravan Gopalkrishnashetty / Iyaswamy, Ashok / Krishnamoorthi, Senthilkumar / Senapati, Sanjib / Malampati, Sandeep / Zhu, Zhou / Su, Cheng-Fu / Liu, Jia / Guan, Xin-Jie / Tong, Benjamin Chun-Kit / Cheung, King-Ho / Tan, Jie-Qiong / Lu, Jia-Hong / Durairajan, Siva Sundara Kumar / Song, Ju-Xian / Li, Min

Phytomedicine. 2022 Feb., v. 96

2022

Abstract: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD).To investigate the tau- ... ...

Abstract	Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD).To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese).By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models.Liquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro.Our pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS).We identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases.
Keywords	Alzheimer disease ; Corydalis yanhusuo ; acetylation ; active sites ; alkaloids ; brain ; cell culture ; centrifugation ; chromatography ; cognition ; computer simulation ; fearfulness ; fluorometry ; heat stress ; heat-shock protein 70 ; heat-shock protein 90 ; herbal medicines ; histone deacetylase ; immunohistochemistry ; mass spectrometry ; mechanism of action ; memory ; pharmacokinetics ; precipitin tests ; ubiquitination
Language	English
Dates of publication	2022-02
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2021.153887
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A stress response p38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of p38.

Yang, Chuanbin / Zhu, Zhou / Tong, Benjamin Chun-Kit / Iyaswamy, Ashok / Xie, Wen-Jian / Zhu, Yu / Sreenivasmurthy, Sravan Gopalkrishnashetty / Senthilkumar, Krishnamoorthi / Cheung, King-Ho / Song, Ju-Xian / Zhang, Hong-Jie / Li, Min

Redox biology

2020 Volume 32, Page(s) 101445

Abstract: TFEB (transcription factor EB) and TFE3 (transcription factor E3) are "master regulators" of autophagy and lysosomal biogenesis. The stress response p38 mitogen-activated protein (MAP) kinases affect multiple intracellular responses including ... ...

Abstract	TFEB (transcription factor EB) and TFE3 (transcription factor E3) are "master regulators" of autophagy and lysosomal biogenesis. The stress response p38 mitogen-activated protein (MAP) kinases affect multiple intracellular responses including inflammation, cell growth, differentiation, cell death, senescence, tumorigenesis, and autophagy. Small molecule p38 MAP kinase inhibitors such as SB202190 are widely used in dissection of related signal transduction mechanisms including redox biology and autophagy. Here, we initially aimed to investigate the links between p38 MAP kinase and TFEB/TFE3-mediated autophagy and lysosomal biogenesis. Unexpectedly, we found that only SB202190, rather than several other p38 inhibitors, promotes TFEB and TFE3 to translocate from the cytosol into the nucleus and subsequently enhances autophagy and lysosomal biogenesis. In addition, siRNA-mediated Tfeb and Tfe3 knockdown effectively attenuated SB202190-induced gene expression and lysosomal biogenesis. Mechanistical studies showed that TFEB and TFE3 activation in response to SB202190 is dependent on PPP3/calcineurin rather than on the inhibition of p38 or MTOR signaling, the main pathway for regulating TFEB and TFE3 activation. Importantly, SB202190 increased intracellular calcium levels, and calcium chelator BAPTAP-AM blocked SB202190-induced TFEB and TFE3 activation as well as autophagy and lysosomal biogenesis. Moreover, endoplasmic reticulum (ER) calcium is required for TFEB and TFE3 activation in response to SB202190. In summary, we identified a previously uncharacterized role of SB202190 in activating TFEB- and TFE3-dependent autophagy and lysosomal biogenesis via ER calcium release and subsequent calcium-dependent PPP3/calcineurin activation, leading to dephosphorylation of TFEB and TFE3. Given the importance of p38 MAP kinase invarious conditions including oxidative stress, the findings collectively indicate that SB202190 should not be used as a specific inhibitor for elucidating the p38 MAP kinase biological functions due to its potential effect on activating autophagy-lysosomal axis.
MeSH term(s)	Autophagy ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Imidazoles ; Lysosomes ; Pyridines ; p38 Mitogen-Activated Protein Kinases/genetics
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Imidazoles ; Pyridines ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole (PVX798P8GI)
Language	English
Publishing date	2020-01-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2020.101445
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Article ; Online: Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition.

Phytomedicine : international journal of phytotherapy and phytopharmacology

2021 Volume 96, Page(s) 153887

Abstract: Background: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD).: Purpose!# ...

Abstract	Background: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD). Purpose: To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese). Study design: By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models. Methods: Liquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro. Results: Our pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS). Conclusion: We identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases.
MeSH term(s)	Alzheimer Disease/drug therapy ; Animals ; Benzophenanthridines ; Berberine Alkaloids ; Disease Models, Animal ; Histone Deacetylase 6/antagonists & inhibitors ; Mice ; Mice, Transgenic ; Molecular Docking Simulation ; tau Proteins
Chemical Substances	Benzophenanthridines ; Berberine Alkaloids ; tau Proteins ; Hdac6 protein, mouse (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98) ; protopine (UIW569HT35)
Language	English
Publishing date	2021-12-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2021.153887
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