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The concept of gene therapy for glaucoma:the dream that has not come true yet

Neural Regeneration Research 2024年第1期19卷 92-99页

作者： Robert Sulak xiaonan liu Adrian Smedowski Department of Physiology Faculty of Medical Sciences in KatowiceMedical University of Silesia in KatowiceKatowicePoland Institute of Biotechnology HiLIFEUniversity of HelsinkiHelsinkiFinland GlaucoTech Co. KatowicePoland

Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

关键词： adeno-associated virus gene editing gene therapy glaucoma IOP lowering IOP-independent mechanisms neuroprotection optic nerve optic neuropathy retinal ganglion cells

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A new era for paclitaxel biosynthesis is coming

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Molecular Plant 2024年第3期17卷 370-371页

作者： xiaonan liu Xiaoxi Zhu Jian Cheng Huifeng Jiang Key Laboratory of Engineering Biology for Low-carbon Manufacturing Tianjin Institute of Industrial BiotechnologyChinese Academy of SciencesTianjin 300308China National Center of Technology Innovation for Synthetic Biology Tianjin 300308China

Paclitaxel(Taxol)stands out as a tetracyclic diterpenoid natural product derived from the endangered plant Taxus.Recognized as a pivotal broad-spectrum anticancer drug,it has garnered widespread attention due to its low yield,intricate structure,unique anticancer mechanism,and remarkable efficacy(Tong et al.,2021).Although chemists achieved the total synthesis of paclitaxel 30 years ago,after decades of research,the natural biosynthetic pathway for its production remains an enigma(Ajikumar et al.,2010;Malci et al.,2023).A recent breakthrough,published in Molecular Plant by Alisdair R.Fernie's team,unveils a minimal gene set of 18 genes required for paclitaxel biosynthesis(Zhang et al.,2023),representing a significant mark toward unraveling the entire biosynthetic pathway and enhancing paclitaxel production efficiency.

关键词： breakthrough representing synthesis

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Diamond-Like Carbon Depositing on the Surface of Polylactide Membrane for Prevention of Adhesion Formation During Tendon Repair

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Nano-Micro Letters 2024年第9期16卷 478-499页

作者： Yao Xiao Zaijin Tao Yufeng Ju Xiaolu Huang Xinshu Zhang xiaonan liu Pavel A.Volotovski Chao Huang Hongqi Chen Yaozhong Zhang Shen liu Department of Orthopaedics Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital600 Yishan RdShanghai 200233People’s Republic of China Shanghai Tongji Hospital 389 Xincun RdShanghai 200065People’s Republic of China Key Laboratory for Thin Film and Microfabrication of Ministry of Education Research Institute of Micro/Nano Science and TechnologyShanghai Jiao Tong UniversityShanghai 200240People’s Republic of China Orthopedic Trauma Department Belarus Republic Scientific and Practical Center for Traumatology and OrthopedicsKizhevatova str.60/4220024 MinskBelarus Shanghai Haohai Biological Technology Limited Liability Company 1386 Hongqiao RdShanghai 200336People’s Republic of China Department of General Surgery Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital600 Yishan RdShanghai 200233People’s Republic of China Shanghai Key Laboratory for High Temperature Materials and Precision Forming School of Materials Science and EngineeringShanghai Jiao Tong UniversityShanghai 200240People’s Republic of China

Post-traumatic peritendinous adhesion presents a significant challenge in clinical medicine.This study proposes the use of diamond-like carbon(DLC)deposited on polylactic acid(PLA)membranes as a biophysical mechanism for anti-adhesion barrier to encase ruptured tendons in tendon-injured rats.The results indicate that PLA/DLC composite membrane exhibits more efficient anti-adhesion effect than PLA membrane,with histological score decreasing from 3.12±0.27 to 2.20±0.22 and anti-adhesion effectiveness increasing from 21.61%to 44.72%.Mechanistically,the abundant C=O bond functional groups on the surface of DLC can reduce reactive oxygen species level effectively;thus,the phosphorylation of NF-κB and M1 polarization of macrophages are inhibited.Consequently,excessive inflammatory response augmented by M1 macrophage-originated cytokines including interleukin-6(IL-6),interleukin-1β(IL-1β),and tumor necrosis factor-α(TNF-α)is largely reduced.For biocompatibility evaluation,PLA/DLC membrane is slowly absorbed within tissue and displays prolonged barrier effects compared to traditional PLA membranes.Further studies show the DLC depositing decelerates the release of degradation product lactic acid and its induction of macrophage M2 polarization by interfering esterase and PLA ester bonds,which further delays the fibrosis process.It was found that the PLA/DLC membrane possess an efficient biophysical mechanism for treatment of peritendinous adhesion.

关键词： Diamond-like carbon Reactive oxygen species scavenging Foreign body reaction Biodegradation Antioxidant Peritendinous adhesion

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Supported catalytic packing prepared from ceramic packing for reactive distillation of ethyl acetate

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Chinese Journal of Chemical Engineering 2022年第10期50卷 205-214页

作者： Zhiwei Wang Jiannan Shi xiaonan liu Zhikai Cao Yong Sha Department of Chemical and Biochemical Engineering College of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005China

In this work,a strategy of"etching-modification filling-graft copolymerization"was proposed to load the acidic ionic polyionic liquid on the smooth ceramic surface.In this way,commercial ceramic Raschig rings were successfully transformed into the supported catalytic packing for the reactive distillation,and were further evaluated with esterification reaction of ethyl acetate by means of the fully mixed reactor,the ultrasonic destruction,the cyclic catalysis reaction and the lab-scale distillation column experiment.This catalyst coating has good adhesion with the substrate.It can withstand 24 h of ultrasound damage and shows good stability in three cycle catalytic experiments.This kind of coated catalyst has better catalytic activity than the commercial Amberlyst 15 dry.In the lab-scale reaction distillation,the supported catalyst Raschig ring can achieve a higher conversion in comparison with the tea bag catalytic packing of Amberlyst 15 dry under some conditions.

关键词： Supported catalyticpacking Ethyl acetate Reactive distillation Bonding strength

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Mn-based MXene with high lithium-ion storage capacity

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Nano Research 2024年第5期17卷 4181-4191页

作者： Yanyan Wu Dongqing liu xiaonan Wang Usman Ghani Muhammad Asim Mushtaq Jinfeng Yang Huarui Sun Panagiotis Tsiakaras Xingke Cai School of Science and Ministry of Industry and Information Technology Key Laboratory of Micro-Nano Optoelectronic Information System Harbin Institute of Technology ShenzhenShenzhen 5180552 China Collaborative Innovation Center of Extreme Optics Shanxi UniversityTaiyuan 030006China Institute for Advanced Study Shenzhen UniversityShenzhen 518060China College of Mechatronics and Control Engineering Shenzhen UniversityShenzhen 518060China Laboratory of Alternative Energy Conversion Systems Department of Mechanical EngineeringSchool of EngineeringUniversity of ThessalyPedion Areos 38834Greece

3d-transition metal(Fe,Co,Ni,and Mn)-based MXene materials have been predicted to demonstrate exceptional electrochemical performance because of their good electrical conductivity and the presence of metallic atoms with multiple charge states.However,until now,there have been no reports on MXenes based on Fe,Co,Ni,and Mn,due to the lack of 3d-metal-layered precursors.Herein,we successfully synthesized the first 3d-transition metal-based MXenes,Mn_(2)CT_(x) by exfoliating a layered precursor derived from the anti-perovskite bulk Mn3GaC.The as-prepared Mn_(2)CT_(x) MXene nanosheets were employed as anode materials in lithium-ion batteries,which exhibited stable storage capacity of 764.7 mAh·g^(-1) at 0.5 C,placing its storage capacities at an upper-middle level compared with other reported MXene materials as well as other Mn-based anode materials.Overall,this study opens a new avenue for MXene research by synthesizing 3d-transition metal-based MXenes for electrochemical applications.

关键词： Mn_(3)GaC Mn_(2)CT_(x) MXenes lithium-ion battery anode materials negative fading capacity

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A Branch-independence-based Reliability Assessment Approach for Transmission Systems

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Journal of Modern Power Systems and Clean Energy 2023年第2期11卷 651-661页

作者： Shuonan Hou Pei Zhang Wei Zhang Qian Xiao xiaonan liu Key Laboratory of Smart Grid of Ministry of Education Tianjin UniversityTianjinChina School of Electrical Engineering Beijing Jiaotong UniversityBeijingChina State Key Laboratory of Information Photonics and Optical Communications Beijing University of Posts and TelecommunicationsBeijingChina State Grid Tianjin Electric Power Research Institute TianjinChina

This paper proposes a branch-independence-based reliability assessment approach for transmission systems.The approach consists of branch decoupling and state-space partition techniques.By integrating an impact-increment-based reliability index calculation model and the proposed branch decoupling technique,a proportion of sampled contingency states no longer need to be analyzed using the time-consuming optimal power flow(OPF)algorithm.In this way,the technique speeds up the calculation of reliability indices.Since first-order contingency states have a high probability of being sampled,we propose a state-space partition technique to replace first-order contingency state simulation with first-order contingency state enumeration.Consequently,the calculation of reliability indices is further accelerated by avoiding a large amount of repetitive OPF analyses during simulation process without affecting reliability index accuracy.The validity and applicability of our approach are verified using the IEEE 118-bus and IEEE 145-bus systems.Numerical results indicate that the proposed approach can improve computational efficiency without decreasing accuracy.

关键词： Branch decoupling impact increment optimal power flow(OPF) reliability assessment state-space partition transmission system

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Impact Increment Based Hybrid Reliability Assessment Method for Transmission Systems

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CSEE Journal of Power and Energy Systems 2022年第1期8卷 317-328页

作者： Yunkai Lei Yeguang Sun Kai Hou Pei Zhang Lewei Zhu Xiaoxi Yang xiaonan liu State Grid Sichuan Economic Research Institute Chengdu610000 China School of Electrical and Information Engineering Tianjin UniversityTianjin 300072China State Grid Customer Service Center Tianjin 300072China School of Electrical and Automation Engineering East China Jiaotong UnviersityNanchang 330052China Maritime College Tianjin University of TechnologyTianjin 300384China College of Economics and Management Southwest Petroleum UniversityChengdu 610000China State Grid Tianjin Electric Power Research Institute Tianjin 300072China

This paper proposes an impact-increment-based hybrid(IIHybrid)reliability assessment approach for power transmission systems.The proposed approach integrates the advantages of the impact-increment-based state enumeration method(IISE)and impact-increment-based Monte Carlo simulation(IIMC)to improve computational efficiency and accuracy.The IISE can efficiently assess the impacts of low-order contingencies.The accuracy is,however,sacrificed as highorder contingencies are usually neglected.The IIMC is more suitable for large-scale contingency spaces compared with IISE,although the calculation process is time-consuming.In this paper,the proposed IIHybrid takes advantage of its strengths while avoiding its shortcomings.The IISE and the IIMC are applied to lower and higher contingency spaces respectively.The high-order contingencies elimination technique proposed in our previous studies is still applicable to the IIHybrid.In addition,efficiency can be controlled by modifying the preset parameters to adapt to various scenarios.Case studies are performed on the IEEE 118-bus test system and PEGASE System.The results show that the proposed approach is more efficient and practicable than traditional methods.

关键词： Hybrid method impact-increment reliability assessment transmission system

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Optimization of inter-seasonal nitrogen allocation increases yield and resource-use efficiency in a water-limited wheat-maize cropping system in the North China Plain

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The Crop Journal 2024年第3期12卷 907-914页

作者： xiaonan Zhou Chenghang Du Haoran Li Zhencai Sun Yifei Chen Zhiqiang Gao Zhigan Zhao Yinghua Zhang Zhimin Wang Ying liu College of Agronomy and Biotechnology China Agricultural UniversityBeijing 100193China College of Information and Electrical Engineering China Agricultural UniversityBeijing 100193China Ministerial and Provincial Co-Innovation Centre for Endemic Crops Production with High-Quality and Efficiency in Loess Plateau Taigu 030801ShanxiChina

Winter wheat–summer maize cropping system in the North China Plain often experiences droughtinduced yield reduction in the wheat season and rainwater and nitrogen(N)fertilizer losses in the maize season.This study aimed to identify an optimal interseasonal water-and N-management strategy to alleviate these losses.Four ratios of allocation of 360 kg N ha^(-1)between the wheat and maize seasons under one-time presowing root-zone irrigation(W0)and additional jointing and anthesis irrigation(W2)in wheat and one irrigation after maize sowing were set as follows:N1(120:240),N2(180:180),N3(240:120)and N4(300:60).The results showed that under W0,the N3 treatment produced the highest annual yield,crop water productivity(WPC),and nitrogen partial factor productivity(PFPN).Increased N allocation in wheat under W0 improved wheat yield without affecting maize yield,as surplus nitrate after wheat harvest was retained in the topsoil layers and available for the subsequent maize.Under W2,annual yield was largest in the N2 treatment.The risk of nitrate leaching increased in W2 when N application rate in wheat exceeded that of the N2 treatment,especially in the wet year.Compared to W2N2,the W0N3 maintained 95.2%grain yield over two years.The WPCwas higher in the W0 treatment than in the W2 treatment.Therefore,following limited total N rate,an appropriate fertilizer N transfer from maize to wheat season had the potential of a“triple win”for high annual yield,WPCand PFPN in a water-limited wheat–maize cropping system.

关键词： Cropping system Water-saving irrigation North China Plain Nitrogen optimization Sustainable intensification

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Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer

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Chinese Medical Journal 2024年第2期137卷 209-221页

作者： Shi Qiu Yaqi Qiu Linghui Deng Ling Nie Liming Ge xiaonan Zheng Di Jin Kun Jin Xianghong Zhou Xingyang Su Boyu Cai Jiakun Li Xiang Tu Lina Gong Liangren liu Zhenhua liu Yige Bao Jianzhong Ai Tianhai Lin Lu Yang Qiang Wei Department of Urology Institute of UrologyNational Clinical Research Center for Geriatrics and Center of Biomedical Big DataWest China Hospital of Sichuan UniversityChengduSichuan 610041China Department of Molecular Oncology Institute of Oncology Research(IOR)Oncology Institute of Southern Switzerland(IOSI)Bellinzona 6500Switzerland Department of Science and Drug Technology University of TurinTurinItaly National Clinical Research Center of Geriatrics The Center of Gerontology and GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610000China Department of Pathology West China HospitalSichuan UniversityChengduSichuan 610041China Department of Pharmaceutics and Bioengineering School of Chemical EngineeringSichuan UniversityChengduSichuan 610000China

Background:Bladder cancer,characterized by a high potential of tumor recurrence,has high lifelong monitoring and treatment costs.To date,tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types.Nonetheless,the existence of soft tumor cells in bladder tumors remains elusive.Thus,our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods:The stiffness of bladder cancer cells was determined by atomic force microscopy(AFM).The modified microfluidic chip was utilized to separate soft cells,and the 3D Matrigel culture system was to maintain the softness of tumor cells.Expression patterns of integrinβ8(ITGB8),protein kinase B(AKT),and mammalian target of rapamycin(mTOR)were determined by Western blotting.Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59(TRIM59).The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.Results:Using our newly designed microfluidic approach,we identified a small fraction of soft tumor cells in bladder cancer cells.More importantly,the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens,in which the number of soft tumor cells was associated with tumor relapse.Furthermore,we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells.Simultaneously,we detected a remarkable up-regulation in ITGB8,TRIM59,and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions:The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness.Meanwhile,the soft tumor cells become more sensitive to chemotherapy after stiffening,that offers new insights fo

关键词： Soft tumor cells 3D Matrigel Stemness Non-muscle invasive bladder neoplasms Microfluidic analytical techniques

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PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α-GLUT2 pathway

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2391-2405页

作者： Peihua liu Ling Jiang Weimin Kong Qiushi Xie Ping Li xiaonan liu Jiayi Zhang Ming liu Zhongjian Wang Liang Zhu Hanyu Yang Ying Zhou Jianjun Zou Xiaodong liu Li liu Center of Drug Metabolism and Pharmacokinetics School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China Department of Clinical Pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor(PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha(HNF4 a)-glucose transporter 2(GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 a expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 a expression, while silencing PXR upregulated HNF4 a and GLUT2 expression.Silencing HNF4 a decreased GLUT2 expression, while overexpressing HNF4 a increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 a reversed the atorvastatininduced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4 a mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4 a downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4 a plasmid increased Slc2 a2 promoter activity. Hnf4 a silencing or pregnenolone-16 a-carbonitrile(PCN) suppressed the Slc2 a2 promoter activity by decreasing HNF4 a recruitment to the Slc2 a2 promoter. Liver-specific Hnf4 a deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 a and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 aGLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

关键词： Pregnane X receptor Hepatocyte nuclear factor4-alpha Glucose transporter 2 Hepatic glucose uptake Diabetes Drug-induced hyperglycemia

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