Publications by authors named "Ju-Xian Song"

42 Publications

TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.

Acta Pharmacol Sin 2021 Aug 20. Epub 2021 Aug 20.

Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆--prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.
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http://dx.doi.org/10.1038/s41401-021-00711-7DOI Listing
August 2021

Qingyangshen mitigates amyloid-β and Tau aggregate defects involving PPARα-TFEB activation in transgenic mice of Alzheimer's disease.

Phytomedicine 2021 Oct 12;91:153648. Epub 2021 Jul 12.

Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address:

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology.

Purpose: The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation.

Methods: QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro.

Results: Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aβ and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro.

Conclusion: QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery.
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http://dx.doi.org/10.1016/j.phymed.2021.153648DOI Listing
October 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Electroacupuncture ameliorates beta-amyloid pathology and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB).

Autophagy 2021 Feb 23:1-15. Epub 2021 Feb 23.

Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.

Alzheimer disease (AD) is the most prevalent neurodegenerative disorder leading to dementia in the elderly. Unfortunately, no cure for AD is available to date. Increasing evidence has proved the roles of misfolded protein aggregation due to impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) in the pathogenesis of AD, and thus making TFEB (transcription factor EB), which orchestrates ALP, as a promising target for treating AD. As a complementary therapy, acupuncture or electroacupuncture (EA) has been commonly used for treating human diseases. Although the beneficial effects of acupuncture for AD have been primarily studied both pre-clinically and clinically, the real efficacy of acupuncture on AD remains inconclusive and the underlying mechanisms are largely unexplored. In this study, we demonstrated the cognitive-enhancing effect of three-needle EA (TNEA) in an animal model of AD with beta-amyloid (Aβ) pathology (5xFAD). TNEA reduced APP (amyloid beta (A4) precursor protein), C-terminal fragments (CTFs) of APP and Aβ load, and inhibited glial cell activation in the prefrontal cortex and hippocampus of 5xFAD. Mechanistically, TNEA activated TFEB via inhibiting the AKT-MAPK1-MTORC1 pathway, thus promoting ALP in the brains. Therefore, TNEA represents a promising acupuncture therapy for AD, via a novel mechanism involving TFEB activation. Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; AKT1: thymoma viral proto-oncogene 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta (A4) precursor protein; BACE1: beta-site APP cleaving enzyme 1; CQ: chloroquine; CTFs: C-terminal fragments; CTSD: cathepsin D; EA: electroacupuncture; FC: fear conditioning; GFAP: glial fibrillary acidic protein; HI: hippocampus; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPT: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNEA: three-needle electroacupuncture.
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http://dx.doi.org/10.1080/15548627.2021.1886720DOI Listing
February 2021

Traditional Chinese medicine compounds regulate autophagy for treating neurodegenerative disease: A mechanism review.

Biomed Pharmacother 2021 Jan 11;133:110968. Epub 2020 Nov 11.

Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region. Electronic address:

Neurodegenerative diseases (NDs) are common chronic diseases related to progressive damage of the nervous system. Globally, the number of people with an ND is dramatically increasing consistent with the fast aging of society and one of the common features of NDs is the abnormal aggregation of diverse proteins. Autophagy is the main process by which misfolded proteins and damaged organelles are removed from cells. It has been found that the impairment of autophagy is associated with many NDs, suggesting that autophagy has a vital role in the neurodegeneration process. Recently, more and more studies have reported that autophagy inducers display a protective role in different ND experimental models, suggesting that enhancement of autophagy could be a potential therapy for NDs. In this review, the evidence for beneficial effects of traditional Chinese medicine (TCM) regulate autophagy in the models of Alzheimer's disease (AD), Parkinson's disease (PD), and other NDs are presented and common autophagy-related mechanisms are identified. The results demonstrate that TCM which regulate autophagy are potential therapeutic candidates for ND treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110968DOI Listing
January 2021

Transcription factor EB: an emerging drug target for neurodegenerative disorders.

Drug Discov Today 2021 01 22;26(1):164-172. Epub 2020 Oct 22.

Mr. and Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address:

The discovery of transcription factor EB (TFEB) as a master regulator of the autophagy-lysosomal pathway (ALP) has triggered increasing numbers of studies that aim to explore the therapeutic potential of targeting TFEB to treat neurodegenerative disorders (NDs) such as Alzheimer's disease and Parkinson's disease. So far, the findings are exciting and promising. Here, we delineate the dysfunction of the TFEB-mediated ALP in NDs, and we summarize small molecules that have been identified as TFEB activators, along with their protective effects in NDs. We discuss the molecular mechanisms and targets, and the pros and cons of these TFEB activators from the perspective of drug development. Specific and potent small-molecule TFEB activators with ideal brain bioavailability could provide a method for treating NDs.
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http://dx.doi.org/10.1016/j.drudis.2020.10.013DOI Listing
January 2021

NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation.

Autophagy 2021 05 16;17(5):1112-1130. Epub 2020 Jun 16.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.

NRBF2 is a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Our previous study has revealed its role in regulating ATG14-associated PtdIns3K activity for autophagosome initiation. In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation. Our data showed that NRBF2 localized at autolysosomes, and loss of NRBF2 impaired autophagosome maturation. Mechanistically, NRBF2 colocalizes with RAB7 and is required for generation of GTP-bound RAB7 by interacting with RAB7 GEF CCZ1-MON1A and maintaining the GEF activity. Specifically, NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Finally, we showed that NRBF2 is involved in APP-CTF degradation and amyloid beta peptide production by maintaining the interaction between APP and the CCZ1-MON1A-RAB7 module to facilitate the maturation of APP-containing vesicles. Overall, our study revealed a pivotal role of NRBF2 as a new RAB7 effector in modulating autophagosome maturation, providing insight into the molecular mechanism of NRBF2-PtdIns3K in regulating RAB7 activity for macroautophagy/autophagy maturation and Alzheimer disease-associated protein degradation.. 3xTg AD, triple transgenic mouse for Alzheimer disease; Aβ, amyloid beta peptide; Aβ amyloid beta peptide 1-40; Aβ amyloid beta peptide 1-42; AD, Alzheimer disease; APP, amyloid beta precursor protein; APP-CTFs, APP C-terminal fragments; ATG, autophagy related; ATG5, autophagy related 5; ATG7, autophagy related 7; ATG14, autophagy related 14; CCD, coiled-coil domain; CCZ1, CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; CHX, cycloheximide; CQ, chloroquine; DAPI, 4',6-diamidino-2-phenylindole; dCCD, delete CCD; dMIT, delete MIT; FYCO1, FYVE and coiled-coil domain autophagy adaptor 1; FYVE, Fab1, YGL023, Vps27, and EEA1; GAP, GTPase-activating protein; GDP, guanine diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanine triphosphate; GTPase, guanosine triphosphatase; HOPS, homotypic fusion and vacuole protein sorting; ILVs, endosomal intralumenal vesicles; KD, knockdown; KO, knockout; LAMP1, lysosomal associated membrane protein 1; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MLVs, multilamellar vesicles; MON1A, MON1 homolog A, secretory trafficking associated; NRBF2, nuclear receptor binding factor 2; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; RILP, Rab interacting lysosomal protein; SNARE, soluble -ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62, sequestosome 1; UVRAG, UV radiation resistance associated; VPS, vacuolar protein sorting; WT, wild type.
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http://dx.doi.org/10.1080/15548627.2020.1760623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143228PMC
May 2021

Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson's disease models.

Cell Death Dis 2020 02 18;11(2):128. Epub 2020 Feb 18.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China.

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
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http://dx.doi.org/10.1038/s41419-020-2322-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028954PMC
February 2020

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

Redox Biol 2020 05 28;32:101445. Epub 2020 Jan 28.

Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.redox.2020.101445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264467PMC
May 2020

A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease.

ACS Nano 2020 02 10;14(2):1533-1549. Epub 2020 Feb 10.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen 361102 , China.

Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.
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http://dx.doi.org/10.1021/acsnano.9b06453DOI Listing
February 2020

Targeting Aggrephagy for the Treatment of Alzheimer's Disease.

Cells 2020 01 28;9(2). Epub 2020 Jan 28.

Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.
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http://dx.doi.org/10.3390/cells9020311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072705PMC
January 2020

NeuroDefend, a novel Chinese medicine, attenuates amyloid-β and tau pathology in experimental Alzheimer's disease models.

J Food Drug Anal 2020 01 8;28(1):132-146. Epub 2019 Oct 8.

Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China. Electronic address:

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β (Aβ) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid β (Aβ) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-β/α), Aβ and 4G8 positive Aβ burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans.
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http://dx.doi.org/10.1016/j.jfda.2019.09.004DOI Listing
January 2020

A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models.

Aging Cell 2020 02 19;19(2):e13069. Epub 2019 Dec 19.

Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.
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http://dx.doi.org/10.1111/acel.13069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996953PMC
February 2020

Autophagy modulator scoring system: a user-friendly tool for quantitative analysis of methodological integrity of chemical autophagy modulator studies.

Autophagy 2020 02 23;16(2):195-202. Epub 2019 Dec 23.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR China.

Over the past 20 years (1999-2019), we have witnessed a rapid increase in publications involving chemical macroautophagy/autophagy modulators. However, an overview of the methodologies used in these studies is still lacking, and methodology flaws are frequently observed in some reports. To provide an objective and quantitative analysis of studies involving autophagy modulators, we present an Autophagy Modulator Scoring System (AMSS), which is designed to evaluate methodological integrity. AMSS-A includes the autophagy characterization by 4 aspects, namely, autophagosome quantification, autophagy-related biochemical changes, autophagy substrate degradation, and autophagic flux. AMSS-B contains the pharmacological and functional characteristics of chemical autophagy modulators, including lysosomal function, drug targets, autophagy-dependent pharmacological effects, and validation in multiple cell lines and models. Our analysis shows that of the 385 studies reporting chemical autophagy modulators, only 142 single studies had examined all 4 aspects of autophagy characterization in AMSS-A, and only 10 out of 142 studies had fulfilled all the AMSS criteria in a single study. A comprehensive analysis of the methodologies used in all the studies was made, along with a summary of studies that demonstrated the highest methodological integrity based on AMSS ranking. To test the reliability of the AMSS, a co-efficiency analysis of scores and co-citation values in the co-citation network was performed, and a significant co-efficiency was obtained. Collectively, AMSS provides insight into the methodological integrity of autophagy modulators studies and also offers a user-friendly toolkit to help choose appropriate assays to characterize autophagy modulators.: 3-MA: 3-methyladenine; AMSS: Autophagy Modulator Scoring System; ATG: autophagy-related; BAF: bafilomycin A; BECN1: beclin 1; CQ: chloroquine; GFP: green fluorescent protein; LC3: microtubule associated protein 1 light chain 3; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate.
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http://dx.doi.org/10.1080/15548627.2019.1704119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984593PMC
February 2020

Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma.

Cancer Lett 2019 04 8;448:117-127. Epub 2019 Feb 8.

Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address:

Studies have shown that hypoxia can induce cytoskeletal injury and remodeling through the activation of the RhoA/ROCK signaling pathway by hypoxia-inducible factor-1α (HIF-1α). Our previous study confirmed that CAPZA1 can modulate EMT by regulating actin cytoskeleton remodeling. However, the relationship between HIF-1α and CAPZA1 has not been illustrated. Therefore, this study aimed to investigate the mechanism by which hypoxia induces the remodeling of the actin cytoskeleton by regulating CAPZA1 in hepatocellular carcinoma (HCC) cells. In the present study, we showed that the low expression of CAPZA1 promotes HCC cell invasion and migration in vitro and in vivo by regulating actin cytoskeleton remodeling to drive EMT. Furthermore, we found that the combination of PIP2 and CAPZA1 enables CAPZA1 to be released from the barbed end of F-actin, which in turn drives the remodeling of the actin cytoskeleton. Finally, we confirmed that hypoxia increases PIP2 levels and its binding to CAPZA1 in HCC cells via the HIF-1α/RhoA/ROCK1 pathway. Thus, CAPZA1 and PIP2 could be therapeutic targets to inhibit the invasion and migration promoted by hypoxia in HCC cells.
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http://dx.doi.org/10.1016/j.canlet.2019.01.042DOI Listing
April 2019

Strategies for brain-targeting liposomal delivery of small hydrophobic molecules in the treatment of neurodegenerative diseases.

Drug Discov Today 2019 02 8;24(2):595-605. Epub 2018 Nov 8.

Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. Electronic address:

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), threaten the health of an ever-growing number of older people worldwide; so far, there are no effective cures. Significant efforts have been devoted to developing new drugs for NDs in recent years, and some small molecules have been shown to be promising in preclinical studies. However, the major challenge for brain-targeting drugs is how to efficiently deliver the drugs across the blood-brain barrier (BBB) to desired targets. To address this issue, liposomal delivery systems have proved to be ideal carriers for neuroprotective small molecules. Here, we summarize recent advances in the brain-targeting liposomal delivery of small hydrophobic molecules (SHMs) and propose strategies for developing liposomal SHMs as disease-modifying neurotherapeutics for NDs.
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http://dx.doi.org/10.1016/j.drudis.2018.11.001DOI Listing
February 2019

Selective autophagy: The new player in the fight against neurodegenerative diseases?

Brain Res Bull 2018 03 16;137:79-90. Epub 2017 Nov 16.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Hong Kong Special Administrative Region. Electronic address:

Autophagy is the lysosome-mediated bulk degradation of cellular components for material recycling to maintain cellular homeostasis. Autophagy was initially regarded as a nonselective process, however, recent evidence indicates that this process can in fact be highly selective, especially for targeting and degrading organelles, invading pathogens and protein aggregates. Recent studies have revealed an intrinsic connection between selective autophagy and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Given the vital roles of selective autophagy in these neurodegenerative diseases, modulation of this process is emerging as a new therapeutic strategy for neuroprotection. This review introduces the concept of selective autophagy, provides an overview of the pathological connection between selective autophagy and neurodegenerative diseases, and discusses approaches to modulate selective autophagy for therapeutic effects against neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.brainresbull.2017.11.009DOI Listing
March 2018

Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation.

Sci Rep 2017 10 12;7(1):13061. Epub 2017 Oct 12.

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong.

Hyperhomocystinemia (HHcy) is known as an independent risk factor for cardiovascular disease. Our previous study showed that ginsenoside Rb1, the major active constituent of ginseng, prevents homocysteine (Hcy)-induced endothelial damage. However, the role of ginsenoside Rb1 in Hcy-induced dysfunction in endothelial progenitor cells (EPCs) remains unknown. In the study, we found that ginsenoside Rb1 reversed the Hcy-induced impairment of adhesive and migratory ability in EPCs which were significantly abolished by CXCR4 antagonist AMD3100 and VEGFR2 inhibitor SU5416. Ginsenoside Rb1 significantly reversed Hcy-induced SDF-1 reduction in the supernatant and in the serum. Ginsenoside Rb1 reversed downregulation of SDF-1 and VEGFR2 protein expression, inhibition of p38MAPK phosphorylation induced by Hcy. Re-endothelialization in balloon-injured carotid arteries significantly increased with EPCs transplant, and was even better with Rb1 treatment. This effect was significantly abolished by AMD3100. AMD3100 also decreased the number of CM-DiI labeled EPCs in injured arteries. Here we show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. These findings demonstrate a novel mechanism of the action of Rb1 that may have value in prevention of HHcy associated cardiovascular disease.
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http://dx.doi.org/10.1038/s41598-017-13436-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638839PMC
October 2017

NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models.

Autophagy 2017 ;13(12):2028-2040

b State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Taipa, Macau SAR , China.

Alzheimer disease (AD) is the most common neurodegenerative disease characterized by the deposition of amyloid plaque in the brain. The autophagy-associated PIK3C3-containing phosphatidylinositol 3-kinase (PtdIns3K) complex has been shown to interfere with APP metabolism and amyloid beta peptide (Aβ) homeostasis via poorly understood mechanisms. Here we report that NRBF2 (nuclear receptor binding factor 2), a key component and regulator of the PtdIns3K, is involved in APP-CTFs homeostasis in AD cell models. We found that NRBF2 interacts with APP in vivo and its expression levels are reduced in hippocampus of 5XFAD AD mice; we further demonstrated that NRBF2 overexpression promotes degradation of APP C-terminal fragments (APP-CTFs), and reduces Aβ and Aβ levels in human mutant APP-overexpressing cells. Conversely, APP-CTFs, Aβ and Aβ levels were increased in Nrbf2 knockdown or nrbf2 knockout cells. Furthermore, NRBF2 positively regulates autophagy in neuronal cells and NRBF2-mediated reduction of APP-CTFs levels is autophagy dependent. Importantly, nrbf2 knockout attenuates the recruitment of APP and APP-CTFs into phagophores and the sorting of APP and APP-CTFs into endosomal intralumenal vesicles, which is accompanied by the accumulation of the APP and APP-CTFs into RAB5-positive early endosomes. Collectively, our results reveal the potential connection between NRBF2 and the AD-associated protein APP by showing that NRBF2 plays an important role in regulating degradation of APP-CTFs through modulating autophagy.
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http://dx.doi.org/10.1080/15548627.2017.1379633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788544PMC
July 2019

Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy.

Autophagy 2017 4;13(11):1969-1980. Epub 2017 Oct 4.

d Key Laboratory of Molecular Biophysics, Ministry of Education , College of Life Science and Technology, and the Collaborative Innovation Center for Biomedical Engineering, Huazhong University of Science and Technology , Wuhan , Hubei , China.

Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signaling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B). To identify key regulators, namely, protein kinases, we developed a novel network-based algorithm of in silico Kinome Activity Profiling (iKAP) to computationally infer potentially important protein kinases from phosphorylation networks. Using this algorithm, we observed that Cory or Cory B potentially regulated several kinases. We predicted and validated that Cory, but not Cory B, downregulated a well-documented autophagy kinase, RPS6KB1/p70S6K (ribosomal protein S6 kinase, polypeptide 1). We also discovered 2 kinases, MAP2K2/MEK2 (mitogen-activated protein kinase kinase 2) and PLK1 (polo-like kinase 1), to be potentially upregulated by Cory, whereas the siRNA-mediated knockdown of Map2k2 and Plk1 significantly inhibited Cory-induced autophagy. Furthermore, Cory promoted the clearance of Alzheimer disease-associated APP (amyloid β [A4] precursor protein) and Parkinson disease-associated SNCA/α-synuclein (synuclein, α) by enhancing autophagy, and these effects were dramatically diminished by the inhibition of the kinase activities of MAP2K2 and PLK1. As a whole, our study not only developed a powerful method for the identification of important regulators from the phosphoproteomic data but also identified the important role of MAP2K2 and PLK1 in neuronal autophagy.
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http://dx.doi.org/10.1080/15548627.2017.1371393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788482PMC
June 2019

A Randomized Controlled Trial of Chinese Medicine on Nonmotor Symptoms in Parkinson's Disease.

Parkinsons Dis 2017 23;2017:1902708. Epub 2017 May 23.

School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I-IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score ( = 0.019), mood/cognition ( = 0.005), and reduction in hallucinations ( = 0.024). In addition, post hoc analysis showed a significant reduction in constipation ( < 0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score ( = 0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation.
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http://dx.doi.org/10.1155/2017/1902708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463168PMC
May 2017

Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review.

Phytother Res 2017 Aug 15;31(8):1119-1127. Epub 2017 May 15.

School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, SAR, China.

The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/ptr.5834DOI Listing
August 2017

Neurogenic Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimer's Disease.

Int J Mol Sci 2017 Jan 28;18(2). Epub 2017 Jan 28.

School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.

Hippocampal neurogenesis plays a critical role in the formation of new neurons during learning and memory development. Attenuation of neurogenesis in the brain is one of the primary causes of dementia in Alzheimer's disease (AD), and, conversely, modulating the process of hippocampal neurogenesis benefit patients with AD. Traditional Chinese medicine (TCM), particularly herbal medicine, has been in use for thousands of years in Asia and many regions of the world for the treatment of cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the role of neurotrophic factors, signal transducing factors, epigenetic modulators and neurotransmitters in neurogenesis, and we also discuss the functions of several Chinese herbs and their active molecules in activating multiple pathways involved in neurogenesis. TCM herbs target pathways such as Notch, Wnt, Sonic Hedgehog and receptor tyrosine kinase pathway, leading to activation of a signaling cascade that ultimately enhances the transcription of several important genes necessary for neurogenesis. Given these pathway activating effects, the use of TCM herbs could be an effective therapeutic strategy for the treatment of AD.
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http://dx.doi.org/10.3390/ijms18020272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343808PMC
January 2017

A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition.

Autophagy 2016 08 12;12(8):1372-89. Epub 2016 May 12.

a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.

Autophagy dysfunction is a common feature in neurodegenerative disorders characterized by accumulation of toxic protein aggregates. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models. Currently known TFEB activators are mainly inhibitors of MTOR (mechanistic target of rapamycin [serine/threonine kinase]), which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions. Thus, the identification of TFEB modulators acting without inhibiting the MTOR pathway would be preferred and probably less deleterious to cells. In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR-independent activator of TFEB. Compound C1 specifically binds to TFEB at the N terminus and promotes TFEB nuclear translocation without inhibiting MTOR activity. By activating TFEB, C1 enhances autophagy and lysosome biogenesis in vitro and in vivo. Collectively, compound C1 is an orally effective activator of TFEB and is a potential therapeutic agent for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1080/15548627.2016.1179404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968239PMC
August 2016

Tianma Gouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson's disease.

Sci Rep 2015 Nov 18;5:16862. Epub 2015 Nov 18.

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.

Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. In addition, the neuroprotective effect of TGY was also evaluated in the human dopaminergic neuroblastoma SH-SY5Y cell line treated with rotenone and the rotenone intoxicated hemi-parkinsonian rats. In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. Conclusively, TGY is neuroprotective in PD models both in vivo and in vitro.
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http://dx.doi.org/10.1038/srep16862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649620PMC
November 2015

Comprehensive urinary metabolomic profiling and identification of potential noninvasive marker for idiopathic Parkinson's disease.

Sci Rep 2015 Sep 14;5:13888. Epub 2015 Sep 14.

Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.

Urine metabolic phenotyping has been associated with the development of Parkinson's disease (PD). However, few studies using a comprehensive metabolomics approach have investigated the correlation between changes in the urinary markers and the progression of clinical symptoms in PD. A comprehensive metabolomic study with robust quality control procedures was performed using gas chromatography - mass spectrometry (GC - MS) and liquid chromatography - mass spectrometry (LC - MS) to characterize the urinary metabolic phenotypes of idiopathic PD patients at three stages (early, middle and advanced) and normal control subjects, with the aim of discovering potential urinary metabolite markers for the diagnosis of idiopathic PD. Both GC-MS and LC-MS metabolic profiles of idiopathic PD patients differed significantly from those of normal control subjects. 18 differentially expressed metabolites were identified as constituting a unique metabolic marker associated with the progression of idiopathic PD. Related metabolic pathway variations were observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism. Comprehensive, successive metabolomic profiling revealed changes in the urinary markers associated with progression of idiopathic PD. This profiling relies on noninvasive sampling, and is complementary to existing clinical modalities.
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http://dx.doi.org/10.1038/srep13888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568456PMC
September 2015

The efficacy and safety of the Chinese herbal medicine Di-Tan decoction for treating Alzheimer's disease: protocol for a randomized controlled trial.

Trials 2015 Apr 30;16:199. Epub 2015 Apr 30.

School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong.

Background: Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is estimated that the global prevalence of dementia will rise from 24.3 million in 2005 to 81.1 million in 2040. AD has a devastating impact on sufferers, caregivers, their communities and the healthcare system in general. "Di-tan decoction" (DTD) is a traditional Chinese medicine (TCM) formula frequently used to treat symptoms that are now defined as AD in clinical treatment. However, the existing evidence for recommending DTD in clinical practice derives from studies that were methodologically flawed. In this study, we aim to determine the efficacy and safety of DTD in AD patients based on a rigidly randomized controlled trial. It will provide critical information on sample size and treatment regimen for conducting a full-scale clinical trial of DTD later.

Methods/design: This study will be a double-blind, randomized, placebo-controlled, add-on trial. After a 2-week run-in period, eligible patients with mild to moderate AD will be recruited and given either DTD or placebo twice daily for 24 weeks with follow-up 6 weeks after the last treatment. An increase of four points or greater on the scores of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAD-cog) will be considered as a positive primary outcome. Total scores of the ADAD-cog, the Chinese version of Mini-Mental State Examination (C-MMSE), and the Chinese version of the Disability Assessment for Dementia (C-DAD) score will be used as secondary outcomes. Adverse events will also be reported.

Discussion: This randomized trial will be the first rigorous empirical study on the efficacy of DTD for treating cognitive symptoms in AD patients. Its success will justify and warrant a large-scale clinical trial to further consolidate the evidence for DTD's efficacy in treating AD.

Trial Registration: Chinese Clinical Trial Registry ( ChiCTR-TRC-12004548 , Date of registration: 22 November 2012).
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http://dx.doi.org/10.1186/s13063-015-0716-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426181PMC
April 2015

LC-MS-based urinary metabolite signatures in idiopathic Parkinson's disease.

J Proteome Res 2015 Jan 9;14(1):467-78. Epub 2014 Oct 9.

Department of Chemistry, Hong Kong Baptist University , Science Tower T1304, Hong Kong SAR, China.

Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). These body fluids include urine; however, the relationship between, specifically, urinary metabolic phenotypes and PD is not fully understood. In this study, urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Our study revealed significant correlation between clinical phenotype and urinary metabolite profile. Metabolic profiles of idiopathic PD patients differed significantly and consistently from normal controls, with related metabolic pathway variations observed in steroidogenesis, fatty acid beta-oxidation, histidine metabolism, phenylalanine metabolism, tryptophan metabolism, nucleotide metabolism, and tyrosine metabolism. In the fruit fly Drosophila melanogaster, the alteration of the kynurenine pathway in tryptophan metabolism corresponded with pathogenic changes in the alpha-synuclein overexpressed Drosophila model of PD. The results suggest that LC-MS-based urinary metabolomic profiling can reveal the metabolite signatures and related variations in metabolic pathways that characterize PD. Consistent PD-related changes across species may provide the basis for understanding metabolic regulation of PD at the molecular level.
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http://dx.doi.org/10.1021/pr500807tDOI Listing
January 2015
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