Publications by authors named "Ming-Yue Wu"

31 Publications

Emerging roles of NRBF2/PI3KC3 axis in maintaining homeostasis of brain and guts.

Neural Regen Res 2022 Feb;17(2):323-324

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao Special Administrative Region, China.

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http://dx.doi.org/10.4103/1673-5374.317973DOI Listing
February 2022

Spinal sensory neurons project onto the hindbrain to stabilize posture and enhance locomotor speed.

Curr Biol 2021 Jun 17. Epub 2021 Jun 17.

Sorbonne Université, Institut du Cerveau (ICM), Inserm U 1127, CNRS UMR 7225, 75013 Paris, France. Electronic address:

In the spinal cord, cerebrospinal fluid-contacting neurons (CSF-cNs) are GABAergic interoceptive sensory neurons that detect spinal curvature via a functional coupling with the Reissner fiber. This mechanosensory system has recently been found to be involved in spine morphogenesis and postural control but the underlying mechanisms are not fully understood. In zebrafish, CSF-cNs project an ascending and ipsilateral axon reaching two to six segments away. Rostralmost CSF-cNs send their axons ipsilaterally into the hindbrain, a brain region containing motor nuclei and reticulospinal neurons (RSNs), which send descending motor commands to spinal circuits. Until now, the synaptic connectivity of CSF-cNs has only been investigated in the spinal cord, where they synapse onto motor neurons and premotor excitatory interneurons. The identity of CSF-cN targets in the hindbrain and the behavioral relevance of these sensory projections from the spinal cord to the hindbrain are unknown. Here, we provide anatomical and molecular evidence that rostralmost CSF-cNs synapse onto the axons of large RSNs including Mauthner cells and V2a neurons. Functional anatomy and optogenetically assisted mapping reveal that rostral CSF-cNs also synapse onto the soma and dendrites of cranial motor neurons innervating hypobranchial muscles. During acousto-vestibular evoked escape responses, ablation of rostralmost CSF-cNs results in a weaker escape response with a decreased C-bend amplitude, lower speed, and deficient postural control. Our study demonstrates that spinal sensory feedback enhances speed and stabilizes posture, and reveals a novel spinal gating mechanism acting on the output of descending commands sent from the hindbrain to the spinal cord.
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http://dx.doi.org/10.1016/j.cub.2021.05.042DOI Listing
June 2021

Evaluate the performance of four artificial intelligence-aided diagnostic systems in identifying and measuring four types of pulmonary nodules.

J Appl Clin Med Phys 2021 Jan 24;22(1):318-326. Epub 2020 Dec 24.

School of Public Health and Management, Chongqing Medical University, Chongqing, China.

Purpose: This study aims to evaluate the performance of four artificial intelligence-aided diagnostic systems in identifying and measuring four types of pulmonary nodules.

Methods: Four types of nodules were implanted in a commercial lung phantom. The phantom was scanned with multislice spiral computed tomography, after which four systems (A, B, C, D) were used to identify the nodules and measure their volumes.

Results: The relative volume error (RVE) of system A was the lowest for all nodules, except for small ground glass nodules (SGGNs). System C had the smallest RVE for SGGNs, -0.13 (-0.56, 0.00). In the Bland-Altman test, only systems A and C passed the consistency test, P = 0.40. In terms of precision, the miss rate (MR) of system C was 0.00% for small solid nodules (SSNs), ground glass nodules (GGNs), and solid nodules (SNs) but 4.17% for SGGNs. The comparable system D MRs for SGGNs, SSNs, and GGNs were 71.30%, 25.93%, and 47.22%, respectively, the highest among all the systems. Receiver operating characteristic curve analysis indicated that system A had the best performance in recognizing SSNs and GGNs, with areas under the curve of 0.91 and 0.68. System C had the best performance for SGGNs (AUC = 0.91).

Conclusion: Among four types nodules, SGGNs are the most difficult to recognize, indicating the need to improve higher accuracy and precision of artificial systems. System A most accurately measured nodule volume. System C was most precise in recognizing all four types of nodules, especially SGGN.
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http://dx.doi.org/10.1002/acm2.13142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856495PMC
January 2021

[Application of unrestrained conscious rats with acute inflammatory ankle pain to study of acupuncture analgesia].

Zhen Ci Yan Jiu 2020 Aug;45(8):645-51

School of Acupuncture-moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 201433.

Objective: To compare the analgesic effect of manual acupuncture(MA) stimulation of "Zusanli" (ST36) in rats with inflammatory pain under unrestrained conscious, restrained and general anesthesia conditions, so as to explore the applicability of unrestrained conscious model in the evaluation of acupuncture analgesia effect.

Methods: Male SD rats were divided into 5 groups: blank control (=9), pain model (=7), unrestrained conscious conditions+MA (=6), restrained conditions+MA (=6), and general anesthesia (GA)+MA(=6). The acute pain model was established by injection of complete Freund's adjuvant (CFA) into the left ankle joint 48 h ahead of acupuncture. Subsequently, a single 20 min session of MA was applied to the left ST36. The mechanical and thermal pain thresholds (MPT and TPT) were determined before and after injection of CFA, and after MA stimulation. In order to evaluate the autonomic behavior activities, rats were randomly divided into blank control (=11), pain model (=11) and conscious-unrestrained conditions +MA (=12) groups. The rats' exploratory movements were assessed by open field tests.

Results: Both MPT and TPT were significantly decreased after injection of CFA in the model group relevant to the blank control group (<0.001), and significantly higher in the three MA groups than in the model group (<0.001). Comparison among the three MA groups showed that both MPT and TPT were significantly higher in the conscious unrestrained conditions+MA group than in the restrained conditions+MA and GA+MA groups (<0.05, <0.01). Open filed tests showed that the total moving distance in the open field and wall climbing times were significantly lower in the model group than in the blank control group (<0.01), and the wall climbing times were obviously more in the unstrained conditions+MA group than in the model group (<0.05). The central area resistance time was significantly shorter in the model group than in the control group (<0.05), and was moderately increased after MA despite no evident significance (>0.05). No significant changes were found in the total moving distance after MA and in the central area moving distance after modeling and MA (>0.05).

Conclusion: MA has a better therapeutic effect in relieving pain and pain-induced depression-like behavior in conscious unrestrained rats than in restrained and GA rats, implying a higher applicability of unrestrained conscious pain model to the assessment of acupuncture analgesia.
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http://dx.doi.org/10.13702/j.1000-0607.190703DOI Listing
August 2020

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

PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation.

Autophagy 2021 05 19;17(5):1096-1111. Epub 2020 Mar 19.

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

NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that mice and macrophages displayed impaired apoptotic cell clearance capability, while adoptive transfer of macrophages to mice alleviated DSS-induced colitis lesions. Mechanistically, NRBF2 is required for the generation of the active form of RAB7 to promote the fusion between phagosomes containing engulfed apoptotic cells and lysosomes via interacting with the MON1-CCZ1 complex and regulating the guanine nucleotide exchange factor (GEF) activity of the complex. Evidence from clinical samples further reveals the physiological role of NRBF2 in maintaining intestinal homeostasis. In biopsies of UC patient colon, we observed upregulated NRBF2 in the colon macrophages and the engulfment of apoptotic cells by NRBF2-positive cells, suggesting a potential protective role for NRBF2 in UC. To confirm the relationship between apoptotic cell clearance and IBD development, we compared TUNEL-stained cell counts in the UC with UC severity (Mayo Score) and observed a strong correlation between the two indexes, indicating that apoptotic cell population in colon tissue correlates with UC severity. The findings of our study reveal a novel role for NRBF2 in regulating apoptotic cell clearance to restrict intestinal inflammation. ANOVA: analysis of variance; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BMDM: bone marrow-derived macrophage; BSA: bovine serum albumin; CD: Crohn disease; CD68: CD68 molecule; CFP: cyan fluorescent protein; CMFDA: 5-chloromethylfluorescein diacetate; Co-IP, co-immunoprecipitation; CPR: C-reactive protein; Cy7: cyanine 7 maleimide; DAB: diaminobezidine 3; DAI: disease activity indexes; DAPI: 4'6-diamidino-2-phenylindole; DMEM: dulbecco's modified eagle's medium; DMSO: dimethyl sulfoxide; DOC: sodium deoxycholate; DSS: dextran sulfate sodium; EDTA: ethylenediaminetetraacetic acid; EGTA: ethylenebis (oxyethylenenitrilo) tetraacetic acid; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; FRET: Förster resonance energy transfer; GDP: guanine dinucleotide phosphate; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; GTP: guanine trinucleotide phosphate; GWAS: genome-wide association studies; HEK293: human embryonic kidney 293 cells; HRP: horseradish peroxidase; IBD: inflammatory bowel disease; IgG: immunoglobin G; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; IRGM: immunity related GTPase M; ITGAM/CD11b: integrin subunit alpha M; KO: knockout; LRRK2: leucine rich repeat kinase 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MPO: myeloperoxidase; NaCl: sodium chloride; NEU: neutrophil; NOD2: nucleotide binding oligomerization domain containing 2; NP40: nonidet-P40; NRBF2: nuclear receptor binding factor 2; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PE: P-phycoerythrin; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SDS-PAGE: sodium dodecylsulphate-polyacrylamide gel electrophoresis; TBST: tris-buffered saline Tween-20; Tris-HCl: trihydroxymethyl aminomethane hydrochloride; TUNEL: TdT-mediated dUTP nick-end labeling; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WB: western blotting; WT: wild type; YFP: yellow fluorescent protein.
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http://dx.doi.org/10.1080/15548627.2020.1741332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143223PMC
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

Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis.

Cells 2019 12 27;9(1). Epub 2019 Dec 27.

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

Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function. This review focuses on the role of autophagy, both as nonselective and selective forms, in the regulation of the inflammatory and phagocytotic functions of macrophages. Specifically, the roles of autophagy in pattern recognition, cytokine release, inflammasome activation, macrophage polarization, LC3-associated phagocytosis, and xenophagy are comprehensively reviewed. The roles of autophagy receptors in the macrophage function regulation are also summarized. Finally, the obstacles and remaining questions regarding the molecular regulation mechanisms, disease association, and therapeutic applications are discussed.
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http://dx.doi.org/10.3390/cells9010070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016593PMC
December 2019

iNOS Interacts with Autophagy Receptor p62 and is Degraded by Autophagy in Macrophages.

Cells 2019 10 15;8(10). Epub 2019 Oct 15.

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

Nitric oxide (NO) is an important mediator of inflammation response and the production of NO has been linked to a variety of diseases, including tumors, inflammation and central nervous system diseases. In macrophages, a high level of NO is generated by iNOS during inflammatory responses triggered by cytokines or pathogens. Autophagy, a cellular bulk degradation process via lysosome, has been implicated in many disease conditions including inflammation. In this study, we have reported the previously unknown role of autophagy in regulating iNOS levels in macrophages, both under basal and Lipopolysaccharides (LPS)-induced conditions. Our data showed that iNOS levels accumulated upon autophagy inhibition and decreased upon autophagy induction. iNOS interacted and co-localized with autophagy receptor p62/SQSTM1, especially under LPS-stimulated condition in macrophages. Moreover, the immunostaining data revealed that iNOS also co-localizes with the autophagosome marker LC3 and lysosome marker LAMP1, especially under lysosomal inhibition conditions, indicating iNOS is an autophagy substrate. Finally, we showed that autophagy negatively regulated the generation of NO in macrophages, which is consistent with the changes of iNOS levels. Collectively, our study revealed a previously unknown mechanism by which autophagy regulates iNOS levels to modulate NO production during inflammation.
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http://dx.doi.org/10.3390/cells8101255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829587PMC
October 2019

Neuroprotective effects of berberine in animal models of Alzheimer's disease: a systematic review of pre-clinical studies.

BMC Complement Altern Med 2019 May 23;19(1):109. Epub 2019 May 23.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, Special Administrative Region of China.

Background: Berberine is an isoquinoline alkaloid extracted from various Berberis species which is widely used in East Asia for a wide range of symptoms. Recently, neuroprotective effects of berberine in Alzheimer's disease (AD) animal models are being extensively reported. So far, no clinical trial has been carried out on the neuroprotective effects of berberine. However, a review of the experimental data is needed before choosing berberine as a candidate drug for clinical experiments. We conducted a systematic review on AD rodent models to analyze the drug effects with minimal selection bias.

Methods: Five online literature databases were searched to find publications reporting studies of the effect of berberine treatment on animal models of AD. Up to March 2018, 15 papers were identified to describe the efficacy of berberine.

Results: The included 15 articles met our inclusion criteria with different quality ranging from 3 to 5. We analyzed data extracted from full texts with regard to pharmacological effects and potential anti-Alzheimer's properties. Our analysis revealed that in multiple memory defects animal models, berberine showed significant memory-improving activities with multiple mechanisms, such as anti-inflammation, anti-oxidative stress, cholinesterase (ChE) inhibition and anti-amyloid effects.

Conclusion: AD is likely to be a complex disease driven by multiple factors. Yet, many therapeutic strategies based on lowering β-amyloid have failed in clinical trials. This suggest that the threapy should not base on a single cause of Alzheimer's disease but rather a number of different pathways that lead to the disease. Overall we think that berberine can be a promising multipotent agent to combat Alzheimer's disease.
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http://dx.doi.org/10.1186/s12906-019-2510-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533761PMC
May 2019

Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation.

Phytomedicine 2019 Aug 30;61:152842. Epub 2019 Jan 30.

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

Background: Parkinson's disease (PD) is an age-dependent progressive movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Accumulation of -synuclein (-syn) positive protein aggregates in the substantia nigra is a pathological hallmark of PD, indicating that protein turnover defect is implicated in PD pathogenesis.

Purpose: This study aims to identify neuroprotective compounds which can alleviate the accumulation of -syn in neuronal cells and dissect the underlying mechanisms.

Methods: High throughput screening was performed by dot blot assay. The degradation of different forms of -syn by candidate compounds were assessed by western blot. The autophagy lysosome pathway and ubiquitin-proteasome system were examined to dissect the degradation pathway. The UPS activity was assessed by cellular UPS substrates degradation assay and biochemical proteasome activity assay. Q-PCR was performed to test the mRNA level of different proteasome subunits. Furthermore, Neuroprotective effect of candidate compound was tested by LDH assay and PI staining.

Results: Through the high throughput screening, harmine was identified as a potent -syn lowering compound. The time-dependent and dose-dependent effects of harmine on the degradation of different forms of -syn were further confirmed. Harmine could dramatically promote the degradation of UPS substrates GFP-CL1, Ub-R-GFP and Ub-G76V-GFP, and activate cellular proteasome activity. Mechanistically, harmine dramatically enhanced PKA phosphorylation to enhance proteasome subunit PSMD1 expression. PKA inhibitor blocked the effects of harmine in activating UPS, up regulating PSMD1 and promoting -syn degradation, indicating that harmine enhances UPS function via PKA activation. Moreover, harmine efficiently rescued cell death induced by over-expression of -syn, via UPS-dependent manner.

Conclusion: Harmine, as a new proteasome enhancer, may have potential to be developed into therapeutic agent against neurodegenerative diseases associated with UPS dysfunction and aberrant proteins accumulation.
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http://dx.doi.org/10.1016/j.phymed.2019.152842DOI Listing
August 2019

High content screening for drug discovery from traditional Chinese medicine.

Chin Med 2019 28;14. Epub 2019 Feb 28.

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

Traditional Chinese medicine (TCM) represents the crystallization of Chinese wisdom and civilization. It has been valued as the renewable source for the discovery of novel drugs, owing to its long-term proved efficacy in human diseases and abundant biologically active components pools. To dissect the mystery of TCM, modern technologies such as omics approaches (proteomics, genomics, metabolomics) and drug screening technologies (high through-put screening, high content screening and virtual screening) have been widely applied to either identify the drug target of TCM or identify the active component with certain bio-activity. The advent of high content screening technology has absolutely contributed to a breakthrough in compounds discovery and influenced the evolution of technology in screening field. The review introduces the concept and principle of high content screening, lists and compares the currently used HCS instruments, and summarizes the examples from ours and others research work which applied HCS in TCM-derived compounds screening. Meanwhile, this article also discusses the advantages and limitations of HSC technology in drug discovery from TCM libraries.
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http://dx.doi.org/10.1186/s13020-019-0228-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394041PMC
February 2019

Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology.

Front Pharmacol 2019 28;10:16. Epub 2019 Jan 28.

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

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the ubiquitin-proteasome system has been linked to its accumulation. In this work, we developed a tetracycline-inducible expression system, with simultaneous induced expression of α-syn-EGFP and a bright red fluorescent protein marker (mCherry) to screen for potential compounds for degrading α-syn. We identified canthin-6-one as an α-syn lowering compound which promoted both wild type and mutants α-syn degradation in an ubiquitin-proteasome-system (UPS) dependent manner. By CRISPR/Cas9 genome-wide screening technology, we identified RPN2/PSMD1, the 26S proteasome non-ATPase regulatory subunit 1, as the targeting gene for pharmacological activity of canthin-6-one. Finally, we showed that canthin-6-one up-regulates PSMD1 and enhances UPS function by activating PKA.
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http://dx.doi.org/10.3389/fphar.2019.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360163PMC
January 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

Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity.

Oncotarget 2017 Sep 8;8(44):77673-77684. Epub 2017 Sep 8.

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

Autophagy is a cellular bulk degradation pathway implicated in various diseases. Inhibition of autophagy has been regarded as a new therapeutic strategy for cancer treatment, especially in combination with chemotherapy. In our study, we identified two natural compounds, dauricine (DAC) and daurisoline (DAS), as two potent autophagy blockers through a high-content screening. DAC and DAS are alkaloids isolated from traditional Chinese medicine . We systematically examined the effects of DAC and DAS on autophagy function in HeLa cells and found that DAC and DAS induced massive formation of autophagic vacuoles and lipidation of LC3. The accumulation of autophagic vacuoles and LC3 lipidation are due to blockage of autophagosome maturation as evidenced by interrupted colocalization of autophagsosome and lysosome, increased GFP-LC3/RFP-LC3 ratio and accumulation of autophagic substrate p62. Moreover, DAC and DAS impaired lysosomal function, as indicated by reduced lysosomal protease activity and increased lysosomal pH values. Importantly, we showed that DAC and DAS strongly inhibited the lysosome V-type ATPase activity. For the therapeutic potential, we found that DAC and DAS blocked the campothecin (CPT)-induced protective autophagy in HeLa cells, and dramatically sensitized the multiple cancer cells to CPT-induced cell death. In conclusion, our result shows that DAC and DAS are autophagy inhibitors which inhibit the lysosomal degradation of auophagic vacuoles, and sensitize the CPT-induced cancer cell death. The study implies the therapeutic potential of DAC and DAS in the treatment of cancers in combination of chemotherapy by inhibiting autophagy.
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http://dx.doi.org/10.18632/oncotarget.20767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652807PMC
September 2017

PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum.

Cell Res 2018 01 20;28(1):90-110. Epub 2017 Oct 20.

Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum. Mutant mice with specific PRRT2 deletion in cerebellar granule cells (GCs) recapitulate the behavioral phenotypes seen in Prrt2-null mice. Furthermore, recording made in cerebellar slices showed that optogenetic stimulation of GCs results in transient elevation followed by suppression of Purkinje cell firing. The anticonvulsant drug carbamazepine used in PKD treatment also relieved PKD-like behaviors in mutant mice. Together, our findings identify PRRT2 as a novel regulator of the SNARE complex and provide a circuit mechanism underlying the PRRT2-related behaviors.
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http://dx.doi.org/10.1038/cr.2017.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752836PMC
January 2018

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

Baicalein prevents 6-OHDA/ascorbic acid-induced calcium-dependent dopaminergic neuronal cell death.

Sci Rep 2017 08 21;7(1):8398. Epub 2017 Aug 21.

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

6-OHDA plus ascorbic acid (AA) has long been used to induce Parkinson's disease in rodents, while only 6-OHDA is commonly used to induce cell damage in cellular PD models. AA was believed to act as an anti-oxidant to prevent the degradation of 6-OHDA; however, some studies suggested that AA dramatically enhanced the selectivity and toxicity of 6-OHDA. To understand the mechanisms by which 6-OHDA/AA induces cell death, we established a 6-OHDA/AA cell toxicity model in human dopaminergic neuroblastoma SH-SY5Y cells. We confirmed that the toxicity of 6-OHDA was dramatically increased in the presence of AA, and the toxicity can be prevented by a flavonoid, baicalein. Mechanistically, our research reveals that 6-OHDA/AA induces cell death mainly through the interruption of intracellular calcium homeostasis, which leads to calpain activation and mitochondrial damage. Baicalein prevents 6-OHDA/AA-induced intracellular calcium elevation as well as consequent mitochondria damage. Taken together, our study confirms that 6-OHDA/AA is a more sensitive model for inducing neuronal lesion in vitro and reveals the central role of intracellular calcium in 6-OHDA/AA-induced cell death. Our studies further show that baicalein prevents 6-OHDA/AA-induced cell death by inhibiting intracellular calcium elevation.
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http://dx.doi.org/10.1038/s41598-017-07142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566482PMC
August 2017

Associations between matrix metalloproteinase gene polymorphisms and glaucoma susceptibility: a meta-analysis.

BMC Ophthalmol 2017 Apr 21;17(1):48. Epub 2017 Apr 21.

Department of Neurology, Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, China.

Background: Matrix metalloproteinases (MMPs) polymorphisms have been implicated in the pathogenesis of glaucoma risk. However, the results were controversial. We performed a meta-analysis to evaluate the precise associations between MMPs polymorphisms and glaucoma risk.

Methods: Related studies were reviewed by searching electronic databases within four databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between the most common polymorphisms of MMPs and glaucoma risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power.

Results: Overall, 11 selected articles involving 2,388 cases and 2,319 controls were included in this meta-analysis. Significant associations were only found between MMP-9 rs17576 G > A polymorphism (GA vs. GG: OR = 0.80, 95%CI = 0.67-0.97, P = 0.02, I = 0%), MMP-9 rs3918249 C > T polymorphism (TT vs. CC + CT: OR = 0.71, 95%CI = 0.51-0.98, P = 0.04, I = 0%) and glaucoma risk in the general population. Subgroup analysis also suggested that MMP-9 rs17576 G > A was related to glaucoma in the Caucasian population (GA vs. GG: OR = 0.67, 95%CI = 0.45-1.00, P = 0.05; GA + AA vs. GG: OR = 0.66, 95%CI = 0.45-0.97, P = 0.03, I = 0%).

Conclusions: Our meta-analysis demonstrates that MMP-9 rs17576 G > A polymorphism might be a protective factor against the development of glaucoma in Caucasian population.
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http://dx.doi.org/10.1186/s12886-017-0442-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401566PMC
April 2017

Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases.

J Ethnopharmacol 2016 Dec 26;194:861-876. Epub 2016 Oct 26.

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

Ethnopharmacological Relevance: Traditional Chinese medicine (TCM), an ancient yet still alive medicinal system widely used in East Asia, has played an essential role in health maintenance and diseases control, for a wide range of human chronic diseases like cancers and neurodegenerative diseases. TCM-derived compounds and extracts attract wide attention for their potential application as therapeutic agents against above mentioned diseases.

Aim Of Review: Recent years the enthusiasm in searching for autophagy regulators for human diseases has yielded many positive hits. TCM-derived compounds as important sources for drug discovery have been widely tested in different models for autophagy modulation. Here we summarize the current progress in the discovery of natural autophagy regulators from TCM for the therapeutic application in cancer and neurodegenerative disease models, aiming to provide the direct link from traditional use to new pharmacological application.

Methods: The present review collected the literature published during the recent 10 years which studied the effect of TCM-derived compounds or extracts on autophagy regulation from PubMed, Web of Science, Google Scholar and Science Direct. The names of chemical compounds studied in this article are corresponding to the information in journal plant list.

Results: In this review, we give a brief introduction about the autophagy and its roles in cancer and neurodegenerative disease models and describe the molecular mechanisms of autophagy modulation. We also make comprehensive lists to summarize the effects and underlying mechanisms of TCM-derived autophagy regulators in cancer and neurodegenerative disease models. In the end of the review, we discuss the current strategies, problems and future direction for TCM-derived autophagy regulators in the treatment of human diseases.

Conclusions: A number of data from in vivo and in vitro models indicated TCM derived compounds and extracts hold great potential for the treatment of human diseases including cancers and neurodegenerative diseases. Autophagy, as a novel and promising drug target involved in a wide range of human diseases, can be modulated by many TCM derived agents, indicating autophagy modulation may be an important mechanism underlying the therapeutic effect of TCM in treating diseases. Furthermore, we look forward to seeing the discovery of ideal autophagy modulators from TCM with considerably higher selectivity for the treatment of human diseases.
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http://dx.doi.org/10.1016/j.jep.2016.10.069DOI Listing
December 2016

MAL62 overexpression and NTH1 deletion enhance the freezing tolerance and fermentation capacity of the baker's yeast in lean dough.

Microb Cell Fact 2016 Apr 4;15:54. Epub 2016 Apr 4.

Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Industrial Microbiology Key Laboratory, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China.

Background: Trehalose is related to several types of stress responses, especially freezing response in baker's yeast (Saccharomyces cerevisiae). It is desirable to manipulate trehalose-related genes to create yeast strains that better tolerate freezing-thaw stress with improved fermentation capacity, which are in high demand in the baking industry.

Results: The strain overexpressing MAL62 gene showed increased trehalose content and cell viability after prefermention-freezing and long-term frozen. Deletion of NTH1 in combination of MAL62 overexpression further strengthens freezing tolerance and improves the leavening ability after freezing-thaw stress.

Conclusions: The mutants of the industrial baker's yeast with enhanced freezing tolerance and leavening ability in lean dough were developed by genetic engineering. These strains had excellent potential industrial applications.
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http://dx.doi.org/10.1186/s12934-016-0453-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819290PMC
April 2016

Asymmetric Construction of Spirooxindoles by Organocatalytic Multicomponent Reactions Using Diazooxindoles.

Angew Chem Int Ed Engl 2015 Aug 2;54(32):9409-13. Epub 2015 Jul 2.

Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055 (P. R. China).

The first highly diastereo- and enantioselective multicomponent reaction of diazooxindoles, nitrosoarenes, and nitroalkenes using a newly developed hydrogen-bond catalyst has been successfully developed for the efficient construction of a series of spirooxindole derivatives with excellent functional-group tolerance. Spirooxindoles are formed in excellent yields and stereoselectivities, and the method represents an unprecedented approach for trapping the active intermediate with a nitroalkene to form biologically important compounds having three contiguous stereogenic centers with excellent asymmetric induction.
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http://dx.doi.org/10.1002/anie.201504640DOI Listing
August 2015

Highly enantioselective kinetic resolution of axially chiral BINAM derivatives catalyzed by a Brønsted acid.

Angew Chem Int Ed Engl 2014 Apr 3;53(14):3684-7. Epub 2014 Mar 3.

Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055 (China).

A highly efficient strategy for the kinetic resolution of axially chiral BINAM derivatives involving a chiral Brønsted acid-catalyzed imine formation and transfer hydrogenation cascade process was developed. The kinetic resolution provides a convenient route to chiral BINAM derivatives in high yields with excellent enantioselectivities.
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http://dx.doi.org/10.1002/anie.201310562DOI Listing
April 2014

Enhanced production of 2,3-butanediol by overexpressing acetolactate synthase and acetoin reductase in Klebsiella pneumoniae.

Biotechnol Appl Biochem 2014 Nov-Dec;61(6):707-15. Epub 2014 Apr 29.

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, People's Republic of China; Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin, People's Republic of China; Tianjin Industrial Microbiology Key Laboratory, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, People's Republic of China.

Mutants with overexpression of α-acetolactate synthase (ALS), α-acetolactate decarboxylase, and acetoin reductase (AR), either individually or in combination, were constructed to improve 2,3-butanediol (2,3-BD) production in Klebsiella pneumoniae. The recombinant strains were characterized in terms of the enzyme activity, 2,3-BD yield, and expression levels. The recombinant K. pneumoniae strain (KG-rs) that overexpressed both ALS and AR showed an improved 2,3-BD yield. When cultured in the media with five different carbon sources (glucose, galactose, fructose, sucrose, and lactose), the mutant exhibited higher 2,3-BD productivity and production than the parental strain in all the tested carbon sources except for lactose. The 2,3-BD production of KG-rs in a batch fermentation with glucose as the carbon source was 12% higher than that of the parental strain.
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http://dx.doi.org/10.1002/bab.1217DOI Listing
August 2015

Direct access to α-trifluoromethyl enones via efficient copper-catalyzed trifluoromethylation of Meyer-Schuster rearrangement.

Org Lett 2014 Feb 27;16(3):1000-3. Epub 2014 Jan 27.

Department of Chemistry South University of Science and Technology of China , Shenzhen, 518055, P. R. China.

A novel domino copper-catalyzed trifluoromethylated Meyer-Schuster rearrangement reaction with Togni's reagent was developed, leading to α-trifluormethyl (CF3) enone products with moderate to good yields. Furthermore, α-CF3 enones can be transformed toward important trifluoromethyl heterocyclic motifs in a one-pot version.
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http://dx.doi.org/10.1021/ol403741mDOI Listing
February 2014

Quantitative assessment of the influence of CYP1B1 polymorphisms and head and neck squamous cell carcinoma risk.

Tumour Biol 2014 Apr 17;35(4):3891-7. Epub 2013 Dec 17.

Institute of Stomatology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China.

The associations between CYP1B1 polymorphisms and head and neck squamous cell carcinoma (HNSCC) risk have been conflicting. We therefore performed a meta-analysis to derive a more precise relationship. Six published case-control studies were collected; odds ratios (ORs) with 95% confidence interval (CI) were used to assess the association between CYP1B1 Leu432Val, Asn453Ser polymorphisms, and HNSCC risk. The Sensitivity analysis and publication bias also were performed to guarantee the statistical power. Overall, the pooled OR with 95% CIs indicated that CYP1B1 Leu432Val polymorphism was significantly related with HNSCC risk (for Val vs. Leu: OR = 1.13, 95% CI = 1.03-1.25, P = 0.014, P(heterogeneity) = 0.141; for Val/Val vs. Leu/Leu: OR = 1.30, 95% CI = 1.06-1.60, P = 0.013, P heterogeneity = 0.253; for Val/Val vs. Leu/Leu + Leu/Val: OR = 1.23, 95% CI = 1.05-1.46, P = 0.013, P(heterogeneity) = 0.456). The similar results were also been found in succeeding analysis of HWE and stratified analysis of Caucasian population. Furthermore, no significant association between CYP1B1 Asn453Ser polymorphism and HNSCC risk was found in this meta-analysis. In conclusion, our meta-analysis demonstrates that CYP1B1 Leu432Val polymorphism may be a risk factor for developing HNSCC.
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http://dx.doi.org/10.1007/s13277-013-1516-2DOI Listing
April 2014

Cytompatibility assessment of the surface of titanium after phosphorylation.

Biomed Mater Eng 2014 ;24(1):659-71

Stomatologic Hospital & College, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China.

In this study, orthophosphoric acid (H3PO4) in the treatment of porous titanium (Ti) is investigated and the ability of rat bone marrow stromal cells (BMSCs) is assessed to proliferate and differentiate on these modified surfaces in vitro. To improve the cytocompatibility of Ti surfaces, pure Ti was activated commercially by simple chemical pretreatment in H3PO4 with different densities. Next, the phosphorylated specimens were soaked in simulated body fluid (SBF) to study the effect of biomineralization. The3-[4,5-dimethylthiazol-2-y1]-2, 5-diphenytetrazolium bromide (MTT) assay and the measurement of alkaline phosphatase (ALP) activity utilized to assess proliferation and differentiation of BMSCs on exposure to modified Ti surfaces. Scanning electron microscopic (SEM) images showed that the surfaces of the pre-treated samples were characterized by a complex structure which consisted of a mesh-like morphological matrix and an uniform surface with different morphic crystals of titanium dihydrogen orthophosphate (Ti(H2PO4)3). These crystals contained hydroxyl with phosphate residues that resulted in biomineralization of cells. Therefore, BMSCs reveales a well-dispersed morphology on these modified and functionalized Ti surfaces. The viability and ALP activity of BMSCs on these altered biomimetic surfaces are found to be greater than those of the controls. It is concluded that the treatment of Ti by acid etching in orthophosphoric acid is a suitable method to enhance the in vitro proliferation and differentiation of BMSCs.
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http://dx.doi.org/10.3233/BME-130854DOI Listing
June 2014

No association between MTHFR A1298C gene polymorphism and head and neck cancer risk: a meta-analysis based on 9,952 subjects.

Asian Pac J Cancer Prev 2012 ;13(8):3943-7

Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, China.

Objective: Findings for associations between the methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and head and neck cancer risk have been conflicting. We therefore performed a meta-analysis to derive a more precise relationship.

Methods: Ten published case-control studies were collected and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR A1298C polymorphism and head and neck cancer risk. Sensitivity analysis and publication bias assessment also were performed to guarantee the statistical power.

Results: Overall, no significant association between MTHFR A1298C polymorphism and head and neck cancer risk was found in this meta-analysis (C vs. A: OR=1.04, 95%CI=0.87- 1.25, P=0.668, P heterogeneity<0.001; CC vs. AA: OR=1.07, 95%CI=0.70-1.65, P=0.748, P heterogeneity<0.001; AC vs. AA: OR=1.06, 95%CI=0.88-1.27, P=0.565, P heterogeneity<0.001; CC+AC vs. AA: OR=1.06, 95%CI=0.86-1.30, P=0.571, P heterogeneity<0.001; CC vs. AA+AC: OR=1.02, 95%CI=0.69-1.52, P=0.910, P heterogeneity<0.001). Similar results were also been found in succeeding analysis of HWE and stratified analysis of ethnicity.

Conclusions: In conclusion, our meta-analysis demonstrates that MTHFR A1298C polymorphism may not be a risk factor for developing head and neck cancer.
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http://dx.doi.org/10.7314/apjcp.2012.13.8.3943DOI Listing
April 2013

[A study on the effect of biomineralization and phosphorylation performed on the titanium implant surfaces].

Zhonghua Kou Qiang Yi Xue Za Zhi 2012 Jun;47(6):354-8

Department of Internal Medicine of The School Hospital, Anhui Medical University, Hefei 230032, China.

Objective: To suggest a chemical surface treatment for titanium and to initiate the formation of hydroxycarbonated apatite (HCA) on titanium surface during in vitro bioactivity tests in simulated body fluid (SBF).

Methods: To improve the bone-bonding ability of Ti implants, commercially pure titanium (cpTi) by a simple chemical pre-treatment in orthophosphoric acid (H(3)PO(4)) with different density was activated, and then the phosphorylation specimens were soaked in SBF to investigate the function of biomineralization.

Results: The scanning electron microscope (SEM) photographs showed that the surfaces of the pre-treated samples were characterized by a complex construction, which consisted of a mesh-like morphology matrix (a micro-roughened surface) and an uniform surface with different morphous of titanium dihydrogen orthophosphate [Ti(H(2)PO(4))(3)] crystal. After 14 days in SBF a homogeneous biomimetic apatite layer precipitated.

Conclusions: These data suggest that the treatment of titanium by acid etching in orthophosphoric acid is a suitable method to provide the titanium implant with bone-bonding ability.
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http://dx.doi.org/10.3760/cma.j.issn.1002-0098.2012.06.008DOI Listing
June 2012

Effects of allisartan, a new AT(1) receptor blocker, on blood pressure and end-organ damage in hypertensive animals.

Acta Pharmacol Sin 2009 Mar;30(3):307-13

Department of Pharmacology, Second Military Medical University, Shanghai, China.

Aim: To investigate the effects of allisartan, a new angiotensin II type 1 (AT(1)) receptor antagonist, on blood pressure (BP) and end-organ damage (EOD) in hypertensive rats and dogs.

Methods: First, a single dose of allisartan was given intragastrically to evaluate the BP reduction in spontaneously hypertensive rats (SHRs), two kidney-one clip (2K1C) renovascular hypertensive rats and dogs, and Beagle dogs with angiotensin II-induced hypertension. Second, allisartan was mixed in rat chow for long-term treatment. After 4 months of drug administration, rats were instrumented to determine BP and baroreflex sensitivity (BRS). Observation of morphologic changes was used to estimate EOD. Third, the acute toxicity of allisartan was compared with that of losartan in mice.

Results: BP was significantly decreased after intragastric administration of allisartan in SHRs, 2K1C rats, 2K1C dogs and Beagle dogs with angiotensin II-induced hypertension. Compared with the control, SHRs that received long-term treatment with allisartan exhibited an improved BRS and organ protective effects. Mice who were administered allisartan experienced less acute toxicity than those treated with losartan.

Conclusion: Allisartan is highly effective for BP reduction and organ protection with low toxicity.
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http://dx.doi.org/10.1038/aps.2009.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002399PMC
March 2009
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