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Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

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药学学报:英文版 2023年第6期13卷 2701-2714页

作者： Qi Zhu Juxian Song Jia-Yue Chen Zhenwei Yuan Liangfeng Liu Li-Ming Xie Qiwen Liao richard d.ye Xiu Chen yepiao Yan Jieqiong Tan Chris Soon Heng Tan Min Li Jia-Hong Lu State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Medical College of Acupuncture-Moxibustion and Rehabilitation Guangzhou University of Chinese MedicineGuangzhou 510006China Mr.and Mrs.Ko Chi Ming Centre for Parkinson's disease Research School of Chinese MedicineHong Kong Baptist UniversityHongKong 999077China Guangdong Corporate Key Laboratory of High-end Liquid Medicine R&d IndustrializationShaoguan 512028China Limin Pharmaceutical Factory Livzon Pharmaceutical Group Inc.Shaoguan 512028China Kobilka Institute of Innovative drug discovery School of Medicinethe Chinese University of Hong KongShenzhen 518172China Center for Medical Genetics Life Science SchoolCentral South UniversityChangsha 410031China department of Chemistry College of ScienceSouthern University of Science and TechnologyShenzhen 518055China

Parkinson's disease(Pd)is the most common neurodegenerative movement *** is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia ***(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular *** B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing ***,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal ***,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/*** of HMGB1/2 impaired Cory B-induced *** showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated *** applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 ***,in vivo studies with a wild-typeα-syn transgenic drosophila model of Pd and an A53Tα-syn transgenic mouse model of Pd,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral *** together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against Pd.

关键词： Corynoxine B Parkinson's disease Neurodegenerative disease α-Synuclein Autophagy PI3KC3 HMGB1 HMGB2

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Pharmacological insights into autophagy modulation in autoimmune diseases

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3364-3378页

作者： Ming-Yue Wu Er-Jin Wang du Feng Min Li richard d.ye Jia-Hong Lu State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 9999078China Key Laboratory of Protein Modification and degradation State Key Laboratory of Respiratory DiseaseCollege of Basic Medical ScienceGuangzhou Medical UniversityGuangzhou 510000China School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510000China Kobilka Institute of Innovative drug discovery School of Life and Health Sciencesthe Chinese University of Hong KongShenzhen 518000China

As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological ***-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBd),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune *** review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBd,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.

关键词： Autophagy Autoimmune disease Systemic lupus erythematosus Inflammatory bowel disease Rheumatoid arthritis Experimental autoimmune encephalomyelitis Autophagy inducer Autophagy inhibitor

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Serum Amyloid A induces Interleukin-33 expression

Serum Amyloid A induces Interleukin-33 expression

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第八届全国免疫学学术大会

作者： Ziyan Zhu Lei Sun richard d.ye School of pharmacy Shanghai Jiaotong University

Serum amyloid A(SAA) is an acute-phase protein strongly expressed in chronic inflammatory diseases by *** role and mechanisms of SAA in macrophage gene expression have not been fully *** preformed c dNA microarray to identify different gene expression profile under SAA stimulation in *** data showed that a series of cytokines and chemotatic factors were induced by SAA in macrophages, among which the interleukin-33(IL-33) gene was significantly *** this study, we first investigated the effect of SAA on the production of IL-33, an important pro-inflammatory *** showed that stimulation of macrophages with SAA greatly elicited interleukin-33(IL-33) mRNA level in a dose and time-dependent *** up-regulated production of IL-33 protein by SAA was located in nucleus in an intracrine *** addition, we found that the induction of IL-33 by SAA was mediated through TLR2 but not formyl peptide receptor 2(FP R2), involving the activation of NF-κB and JNK signal ***, using truncated mutant of IL-33 promoter and luciferase report assay, we identified NF-κB and AP-1 binding sites within the IL-33 promoter *** immunoprecipitation studies demonstrated that p65/ Rel A and c-fos were recruited to the endogenous IL-33 promoter in SAA-stimulated human *** together, our results shed light on the capacity of SAA to induce IL-33 expression in macrophage and suggest a potential physiological and pathological function of SAA in chronic inflammatory diseases such as rheumatoid arthritis.

关键词： serum amyloid A(SAA) IL-33 macrophages

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SAA induces M2 macrophage-specific gene expression and promotes efferocytosis of apoptotic neutrophils

SAA induces M2 macrophage-specific gene expression and promo...

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第八届全国免疫学学术大会

作者： Lei Sun Huibin Zhou Ziyan Zhu richard d.ye School of Pharmacy Shanghai Jiaotong University

Macrophages play an important role in the quality, duration and magnitude of most inflammatory reactions in a polarized *** alternatively activated macrophages(M2) produce anti-inflammatory cytokines and promote efferocytosis to resolve ***, the determinants that modulate their plasticity remain *** amyloid A(SAA) is an acute-phase protein which induces both anti-inflammatory and pro-inflammatory cytokines during *** this study, we explored the potential involvement of SAA in modulating macrophage *** not only induced the expression of anti-inflammatory M2-specific genes such as IL-10, Arginase-1, Ym-1, Fizz-1, Mrc-1, IL-1 Rn, but also promoted phagocytosis of apoptotic neutrophils(also called efferocytosis), a process that is critical for the resolution of inflammation, in both human peripheral blood mononuclear cells(PBMC) and mouse primary *** experiments with formyl peptide receptor 2(Fpr2) antagonist W RW4 and Fpr2 deficient macrophages, we showed that the induction of M2-specific genes and efferocytosis by SAA were mediated specifically by Fpr2, one of the SAA ***, SAA stimulation resulted in the increase expression and activation of the transcript factor I *** inhibitors of E RK activity abrogated SAA induction upon M2 macrophages and efferocytosis by decreasing the expression and activation of the transcription factor I RF4, suggesting an important role of I RF4 in SAA induced M2 macrophage *** results demonstrate that SAA can induce M2 macrophage-specific genes and promote efferocytosis via Fpr2-E RK-I RF4 signaling, and suggests an alternative mechanism by which SAA is involved in anti-inflammatory responses.

关键词： macrophage polarization serum amyloid A efferocytosis

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Prescribed-Time Nash Equilibrium Seeking for Pursuit-Evasion Game

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IEEE/CAA Journal of Automatica Sinica 2024年第6期11卷 1518-1520页

作者： Lei Xue Jianfeng ye Yongbao Wu Jian Liu d.C.Wunsch Key Laboratory of Measurement and Control of Complex Systems of Engineering Ministry of EducationNanjing 210096 School of Automation Southeast UniversityNanjing 210096China department of Electrical and Computer Engineering Missouri University of Science and TechnologyRollaMO 65409 USA IEEE

dear Editor,This letter is concerned with prescribed-time Nash equilibrium(PTNE)seeking problem in a pursuit-evasion game(PEG)involving agents with second-order *** order to achieve the prior-given and user-defined convergence time for the PEG,a PTNE seeking algorithm has been developed to facilitate collaboration among multiple pursuers for capturing the evader without the need for any global ***,it is theoretically proved that the prescribedtime convergence of the designed algorithm for achieving Nash equilibrium of ***,the effectiveness of the PTNE method was validated by numerical simulation results.A PEG consists of two groups of agents:evaders and *** pursuers aim to capture the evaders through cooperative efforts,while the evaders strive to evade *** is a classic noncooperative *** has attracted plenty of attention due to its wide application scenarios,such as smart grids[1],formation control[2],[3],and spacecraft rendezvous[4].It is noteworthy that most previous research on seeking the Nash equilibrium of the game,where no agent has an incentive to change its actions,has focused on asymptotic and exponential convergence[5]-[7].

关键词： seeking prescribed convergence

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Akt1 phosphorylates β-catenin and is required for optimal IFN-β transcription

Akt1 phosphorylates β-catenin and is required for optimal I...

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第八届全国免疫学学术大会

作者： richard d.ye Benjamin N.Gantner Huali Jin Feng Qian Nissim Hay Bin He Shanghai Jiao Tong University School of Pharmacy University of Illinois at Chicago

Background:Interferon-β(IFN-β) is a critical antiviral cytokine that modulates the systemic immune *** transcriptional induction of IFN-β is a highly regulated process, involving the activation of pattern recognition receptors and their downstream signaling *** Akt family of serine/threonine kinases includes three isoforms, Akt1, Akt2 and *** specific role for the individual Akt isoforms in pattern recognition and signaling remains ***:We sought to determine whether Akt isoforms specifically regulate TLR3-mediated expression of IFN-β.Methods:Akt1-/- mice were used for preparation of macrophages, which were stimulated with TLR3 agonist or exposed to viral *** expression of IFN-β as well as viral clearance was measured.A chemically activated form of Akt1 was used to evaluate its ability to phosphorylate downstream ***:TLR3-mediated expression of IFN-β is blunted in cells lacking *** expression of IFN-β-inducible genes such as CCL5 and CXCL10 was also reduced in Akt1-deficient cells;the induction of TNF-α and CXCL2, whose expression does not rely on IFN-β, was not reduced in the absence of *** from Akt1-/- mice displayed deficient clearance of Herpes simplex virus-1(HSV-1) along with reduced IFN-β *** results demonstrate that Akt1 signals through β-catenin by phosphorylation on serine 552, a site that differs from the GSK3-β phosphorylation *** of a chemically activated version of Akt1, in the absence of other TLR3-dependent signaling, was sufficient for accumulation and phosphorylation of β-catenin at serine ***:These results demonstrate that the Akt1 isoform is required for β-catenin-mediated promotion ofIFN-β transcription downstream of TLR3 activation.

关键词： Akt IFN-β TLR3 β-catenin GSK3-β

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Investigations of Water Flow Behaviors Induced by Local Temperature Variations through a Single Rough Fracture for the Enhanced Geothermal Systems

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Journal of Thermal Science 2024年第3期33卷 1055-1064页

作者： LI Jiawei ye Lin department of Energy and Power Engineering Tsinghua UniversityBeijing100084China School of Power and Energy Northwestern Polytechnical UniversityXi’an710072China

In recent years,Enhanced Geothermal System(EGS)technologies have been applied to the geothermal resources production in the Hot dry Rock(HdR).The core of EGS technologies is to adopt hydraulic fracturing in the reservoir to create a connected network of discrete fractures with the consideration of water as a working fluid for hydraulic fracturing and heat *** paper investigates the characteristics of water flow behaviors through a single rough fracture under different temperature and pressure conditions.A single fracture model with rough fracture surfaces is constructed and then characterized,and influences of the anisotropic factor on the average tortuosity and frictional resistance coefficient of water flow through a single fracture with rough surfaces have been compared and *** consideration of other impacting factors(temperature,pressure,fracture roughness),the impact of mass flow rate has also been *** simulation results present that changes of average tortuosity for water flow through a single rough facture are mainly affected by *** can be observed that higher temperature leads to larger average tortuosity but the frictional resistance coefficient shows an opposite *** for pressure conditions,it is found that effects of pressure on average tortuosity and frictional resistance coefficient is very small,which can be neglected under high pressure ***,the average tortuosity shows a progressively linear relationship with the mass flow *** the contrary,the frictional resistance coefficient has a negative relationship with the mass flow *** is revealed that when the mass flow rate reaches a critical point,the influences of temperature on the frictional resistance coefficient will be *** of single rough fractures with different anisotropic factors show that values of average tortuosity and frictional resistance coefficient have positive relationships with the increase

关键词： single rough fracture tortuosity frictional resistance enhanced geothermal system

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General formalism for dirty extreme-mass-ratio inspirals

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Science China(Physics,Mechanics & Astronomy) 2024年第7期67卷 22-29页

作者： ye Jiang Wen-Biao Han Shanghai Astronomical Observatory Chinese Academy of SciencesShanghai 200030China School of Astronomy and Space Science University of Chinese Academy of SciencesBeijing 100049China School of Fundamental Physics and Mathematical Sciences Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Shanghai Frontiers Science Center for Gravitational Wave detection Shanghai 200240China

detecting the environment around the supermassive black holes and tests of general relativity are important applications of extreme-mass-ratio inspirals(EMRIs).There is still a challenge to efficiently describe various“dirty”impacts on the inspirals,such as dark matter,gas,dipole radiation,and electromagnetic *** this study,we find the inherent linearity of the asymptotic solution of the inhomogeneous Teukolsky *** the basis of this property,we completely decouple the factors of the perturber and the background spacetime in the energy fluxes and *** the new decoupling form,the waveforms of EMRIs with non-geodesic motion in Kerr spacetime can be conveniently *** will help to resolve the environment(including gas,field,dark matter,electromagnetic interaction)around supermassive black holes and test general relativity.

关键词： gravitational wave Teukolsky equation extreme-mass-ratio inspirals

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Cryo-EM structure of activated bile acids receptor TGR5 in complex with stimulatory G protein

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1209-1211页

作者： Geng Chen Xiankun Wang Yunjun Ge Ling Ma Qiang Chen Huihui Liu Yang du richard dye Hongli Hu Ruobing Ren Kobilka Institute of Innovative drug discovery School of Life and Health SciencesThe Chinese University of Hong Kong518172 ShenzhenGuangdongP.R.China School of Life Sciences University of Science and Technology of China230026 AnhuiP.R.China Warshel Institute for Computational Biology The Chinese University of Hong Kong518172 ShenzhenGuangdongP.R.China

dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR *** major TGR5-dependent actions of BAs include maintaining energy homeostasis,regulating glucose/lipids metabolism,as well as immunosuppressive properties.2 TGR5 is identified as a potential therapeutic target for protecting hepatocytes from bile acid overload,preventing atherosclerosis,and inhibiting macrophage inflammation due to its critical role in bile acid ***,elucidation of structural characteristics of TGR5 and its activation mechanism would benefit the discovery of therapeutic drugs for these metabolic disorders.

关键词： bile metabolism TGR5

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Terahertz sensing with a 3d meta-absorbing chip based on two-photon polymerization printing

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Photonics Research 2024年第5期12卷 895-903页

作者： XUEER CHEN LONGFANG ye dAQUAN YU School of Electronic Science and Engineering Xiamen UniversityXiamen 361005China Institute of Electromagnetics and Acoustics Xiamen UniversityXiamen 361005China Xiamen Sky Semiconductor Technology Co. Ltd.Xiamen 361026China

The narrowband meta-absorbers exhibit significantly enhanced electromagnetic confinement capabilities, showcasing broad application prospects in sensing fields. They can be applied for biomarker detection, chemical composition analysis, and monitoring of specific gas in the environment. In this work, we propose a 3d meta-absorber with an out-of-plane plasma mechanism based on a two-photon printing system. Compared to the conventional fabrication of a metal-insulator-metal 2d meta-absorber, the 3d absorber is composed of a metal layer and a resin layer from top to bottom;its manufacturing process is simpler, only including two-photon printing and magnetron sputtering deposition. A noticeable absorbing resonance appears at 0.3142 THz with perfect absorbance with a high Q-factor of 104.67. The theoretical sensitivity to the refractive index of the sensor reaches up to172.5 GHz/RIU, with a figure of merit (FOM) of 19.56. In the experiments, it was validated as a meta-absorber with high sensitivity for doxycycline (dCH). As the dCH concentration increases from 0 to 4 mg/mL, the absorption intensity decreases around 49%, while the resonant frequency shift is around 70 GHz. It reflects the real-time residual content of dCH, and is potentially applied in trace antibiotic detection. The results showcase a perfect narrowband absorption capability with strong electromagnetic confinement in the terahertz spectrum, along with high-Q sensing characteristics of dCH. Compared to 2d metamaterials, the diversity of3d metamaterial significantly expands, and introduces additional effects to provide greater flexibility in manipulating electromagnetic waves. The 3d device offers opportunities for the application of terahertz biochemical sensing.

关键词： absorber printing absorbing

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