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Strategies that regulate LSD1 for novel therapeutics

Acta Pharmaceutica Sinica B 2024年第4期14卷 1494-1507页

作者： Meng Li Mengge Dai Bing Cheng Shaotong Li Enhui Guo Junwei Fu Ting Ma Bin Yu School of Pharmaceutical Sciences&key laboratory of advanced drug preparation technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China College of Chemistry Zhengzhou UniversityZhengzhou 450001China Tianjian laboratory of advanced Biomedical Sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450000China Pingyuan laboratory State Key Laboratory of Antiviral DrugsHenan Normal UniversityXinxiang 453007China State key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Histone methylation plays crucial roles in regulating chromatin structure and gene transcrip-tion in epigenetic modifications.Lysine-specific demethylase 1(LSD1),the first identified histone de-methylase,is universally overexpressed in various diseases.LSD1 dysregulation is closely associated with cancer,viral infections,and neurodegenerative diseases,etc.,making it a promising therapeutic target.Several LSD1 inhibitors and two small-molecule degraders(UM171 and BEA-17)have entered the clinical stage.LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9(H3K4 or H3K9),resulting in either transcription repression or activation.While the roles of LSD1 in transcrip-tional regulation are well-established,studies have revealed that LSDl can also be dynamically regulated by other factors.For example,the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1.Moreover,some post-transcriptional modifica-tions and cellular metabolites can also regulate LSD1 expression or its demethylase activity.Therefore,in this review,we will systematically summarize how proteins involved in the transcriptional corepressor complex,various post-translational modifications,and metabolites act as regulatory factors for LSD1 ac-tivity.

关键词： LSD1 regulation Transcription repression Transcription activation the Corepressor complex Post-transcriptional modifications Metabolites

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Visualization of nasal powder distribution using biomimetic human nasal cavity model

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Acta Pharmaceutica Sinica B 2024年第1期14卷 392-404页

作者： Jiawen Su Yan Liu Hongyu Sun Abid Naeem Huipeng Xu Yue Qu Caifen Wang Zeru Li Jianhua Lu Lulu Wang Xiaofeng Wang Jie Wu Lixin Sun Jiwen Zhang Zhigang Wang Rui Yang Li Wu key laboratory of Modern preparation of TCM Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China key laboratory of Molecular Pharmacology and drug Evaluation School of PharmacyMinistry of EducationYantai UniversityYantai 264005China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201210China Nantong Haimen People’s Hospital Nantong 226199China Yangtze Delta drug advanced Research Institute Nantong 226126China Shenyang Pharmaceutical University Shenyang 110016China National Institutes for Food and drug Control Beijing 100000China Nanjing University of Chinese Medicine Nanjing 210023China

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity.However,no reliable method is currently available to assess its impact on delivery performance.In this study,a biomimetic nasal model based on three-dimensional(3D)reconstruction and three-dimensional printing(3DP)technology was developed for visualizing the deposition of drug powders in the nasal cavity.The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females.The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test.The experimental device produced the most satisfactory results with five spray times.Furthermore,particle sizes and spray angles were found to significantly affect the experimental device’s performance and alter drug distribution,respectively.Additionally,mometasone furoate(MF)nasal spray(NS)distribution patterns were investigated in a goat nasal cavity model and three male goat noses,confirming the in vitro and in vivo correlation.In conclusion,the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

关键词： Nasal drug deposition Nasal drug distribution Nasal drug delivery Biomimetic nasal model Nasal powder Three-dimensional reconstruction Three-dimensional printing Nasal drug distribution

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A nanoagent for concurrent therapy of breast cancer bone metastasis and cancer-induced bone pain through SLC7A11 interruption and photodynamic therapy

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Chinese Chemical Letters 2024年第2期35卷 295-299页

作者： Qi Fu Zhongming Lian Mengya Niu Yaru Huang Yanqiu Ai Long He Dandan Zhang Cuixia Zheng Jian-Jun Yang Lei Wang Dandan Tian Department of Anesthesiology Pain and Perioperative MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Translational Medical Center of Huaihe Hospital Henan UniversityKaifeng 475004China key laboratory of advanced drug preparation technologies Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhou 450001China

Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.

关键词： Breast cancer bone metastasis Cancer-induced bone pain Cystine/glutamate antiporter Sorafenib Photodynamic therapy

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pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 781-794页

作者： Shuai Guo Chunhui Li Changrong Wang Xiaowen Cao Xinyue Liu Xing-Jie Liang Yuanyu Huang Yuhua Weng School of Medical Technology Advanced Research Institute of Multidisciplinary ScienceSchool of Life ScienceKey Laboratory of Molecular Medicine and BiotherapyKey Laboratory of Medical Molecule Science and Pharmaceutics EngineeringBeijing Institute of TechnologyBeijing 100081China School of Pharmacy Shandong New Drug Loading&Release Technology and Preparation Engineering LaboratoryBinzhou Medical UniversityYantai 264003China School of Ophthalmology and Optometry School of Biomedical EngineeringThe Eye HospitalWenzhou Medical UniversityWenzhou 325027China Chinese Academy of Sciences(CAS) Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing 100190China

Small interfering RNA(siRNA)has a promising future in the treatment of ocular diseases due to its high efficiency,specificity,and low toxicity in inhibiting the expression of target genes and proteins.However,due to the unique anatomical structure of the eye and various barriers,delivering nucleic acids to the retina remains a significant challenge.In this study,we rationally design PACD,an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block(A),a siRNA binding block(B)and a pH-responsive block(C).PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing.By evaluating its pH-responsive activity,gene silencing efficiency in retinal cells,intraocular distribution,and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis,we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina.We are surprised to discover that,the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency,excellent gene silencing,and inhibit retinal angiogenesis.Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

关键词： SiRNA Oculardeliverysystem Block polymer Endosomalescape Retinal neovascularization Blood-retinal barrier VEGFA Safety

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Perilipin 5 regulates hepatic stellate cell activation and high-fat diet-induced non-alcoholic fatty liver disease

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Animal Models and Experimental Medicine 2024年第2期7卷 166-178页

作者： Xuecui Yin Lin Dong Xiaohan Wang Zhenzhen Qin Yuying Ma Xiaofei Ke Ya Li Qingde Wang Yang Mi Quanjun Lyu Xia Xu Pengyuan Zheng Youcai Tang Department of Internal Medicine the Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Department of Pediatrics the Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Department of Clinical Nutrition the First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina key laboratory of advanced drug preparation technologies Ministry of Education of ChinaCo-innovation Center of Henan Province for New drug R&D and Preclinical SafetySchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina Department of Pediatrics GastroenterologyHenan Key Laboratory of Rehabilitation MedicineHenan Joint International Research Laboratory of Chronic Liver Injury and Henan Provincial Outstanding Overseas Scientists Chronic Liver Injury Studiothe Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina

Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.

关键词： AMPK apoptosis hepatic stellate cell liver fibrosis perilipin 5

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Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第3期36卷 306-321页

作者： Zhifei Li Huan Zhao Huihui Hu Haili Shang Yongjing Ren Wenhui Qiu Hao Su Huifang Lyu Xiaobing Chen Department of Oncology the Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer Henan University of Traditional Chinese Medicine State key laboratory of Esophageal Cancer Prevention&Treatment Key Laboratory of Advanced Drug Preparation Technologies Ministry of Education School of Pharmaceutical SciencesZhengzhou University The First Affiliated Hospital of Xinxiang Medical University Department of Oncology the Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital

Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

关键词： HER2 gastric cancer trastuzumab drug resistance

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Isotropic sintering shrinkage of 3D glass-ceramic nanolattices:backbone preforming and mechanical enhancement

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International Journal of Extreme Manufacturing 2024年第2期6卷 418-426页

作者： Nianyao Chai Yunfan Yue Xiangyu Chen Zhongle Zeng Sheng Li Xuewen Wang Center of Femtosecond Laser Manufacturing for advanced Materials and Devices State Key Laboratory of Advanced Technology for Materials Synthesis and ProcessingWuhan University of TechnologyWuhan 430070People’s Republic of China National Energy key laboratory for New Hydrogen-Ammonia Energy technologies Foshan Xianhu LaboratoryFoshan 528000People’s Republic of China International School of Materials Science and Engineering Wuhan University of TechnologyWuhan 430070People’s Republic of China

There is a perpetual pursuit for free-form glasses and ceramics featuring outstanding mechanical properties as well as chemical and thermal resistance.It is a promising idea to shape inorganic materials in three-dimensional(3D)forms to reduce their weight while maintaining high mechanical properties.A popular strategy for the preparation of 3D inorganic materials is to mold the organic–inorganic hybrid photoresists into 3D micro-and nano-structures and remove the organic components by subsequent sintering.However,due to the discrete arrangement of inorganic components in the organic-inorganic hybrid photoresists,it remains a huge challenge to attain isotropic shrinkage during sintering.Herein,we demonstrate the isotropic sintering shrinkage by forming the consecutive–Si–O–Si–O–Zr–O–inorganic backbone in photoresists and fabricating 3D glass–ceramic nanolattices with enhanced mechanical properties.The femtosecond(fs)laser is used in two-photon polymerization(TPP)to fabricate 3D green body structures.After subsequent sintering at 1000℃,high-quality 3D glass–ceramic microstructures can be obtained with perfectly intact and smooth morphology.In-suit compression experiments and finite-element simulations reveal that octahedral-truss(oct-truss)lattices possess remarkable adeptness in bearing stress concentration and maintain the structural integrity to resist rod bending,indicating that this structure is a candidate for preparing lightweight and high stiffness glass–ceramic nanolattices.3D printing of such glasses and ceramics has significant implications in a number of industrial applications,including metamaterials,microelectromechanical systems,photonic crystals,and damage-tolerant lightweight materials.

关键词： 3D printing isotropic shrinkage femtosecond laser two-photon polymerization structural glass-ceramics

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Insight into demand-driven preparation of single-atomic mediators for lithium–sulfur batteries

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Journal of Energy Chemistry 2024年第3期90卷 205-219,I0007页

作者： Miaoyu Lu Yifan Ding Zaikun Xue Ziang Chen Yuhan Zou Jingyu Sun College of Energy Soochow Institute for Energy and Materials InnovationsKey Laboratory for Advanced Carbon Materials and Wearable Energy Technologies of Jiangsu ProvinceSoochow UniversitySuzhou 215006JiangsuChina Beijing Graphene Institute Beijing 100095China

Lithium-sulfur(Li-S) batteries have attracted considerable attention as one of the most appealing energy storage systems.Strenuous efforts have been devoted to tackling the tremendous challenges,mainly pertaining to the severe shuttle effect,sluggish redox kinetics and lithium dendritic growth.Single-atomic mediators as promising candidates exhibit impressive performance in addressing these intractable issues.Related research often utilizes a trial-and-error approach,proposing solutions to fabricate single-atomic materials with diversified features.However,comprehensive review articles especially targeting demand-driven preparation are still in a nascent stage.Inspired by these considerations,this review summarizes the design of single-atomic mediators based on the application case-studies in LiS batteries and other metal-sulfur systems.Emerging preparation routes represented by chemical vapor deposition technology are introduced in a demand-oriented classification.Finally,future research directions are proposed to foster the advancement of single-atomic mediators in Li-S realm.

关键词： Single-atom catalyst Lithium–sulfur battery Chemical vapor deposition Demand-driven preparation

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Coupling Au with BO_(x) matrix induced by Closo-boron cluster for electrochemical synthesis of ammonia

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Journal of Energy Chemistry 2024年第6期93卷 471-477,I0012页

作者： Wenjing Liu Nan Yang Yuao Wei Yingjie Yu Jie Chen Mo Wei Yuting Huang Xiaohan Li Linghai Zhang Faisal Saleem Weina Zhang Haibo Zhang Fengwei Huo key laboratory of Flexible Electronics(KLOFE)&Institute of advanced Materials(IAM) School of Flexible Electronics(Future Technologies)Nanjing Tech UniversityNanjing 211816JiangsuChina College of Chemistry and Molecular Sciences Wuhan UniversityWuhan 430072HubeiChina

Au is considered as one of the most promising catalysts for nitrogen reduction reaction(NRR),however maximizing the activity utilization rate of Au and understanding the synergistic effects between Au and carriers pose ongoing challenges.Herein,we systematically explore the synergistic catalytic effect of incorporating Au with boron clusters for accelerating NRR kinetics.An in-situ abinitio strategy is employed to construct B-doped Au nanoparticles(2-6 nm in diameter)loaded on BO_(x) substrates(AuBO_(x)),in which B not only modulates the surface electronic structure of Au but also forms strong coupling interactions to stabilize the nanoparticles.The electrochemical results show that Au-BO_(x) possesses excellent NRR activity(NH_(3) yield of 48.52μg h^(-1)mg_(cat)^(-1),Faraday efficiency of 56.18%),and exhibits high stability and reproducibility throughout the electrocatalytic NRR process.Theoretical calculations reveal that the introduction of B induces the formation of both Au dangling bond and Au-B coupling bond.which considerably facilitates the hydrogenation of~*N_(2)^(-)~*NH_(3).The present work provides a new avenue for the preparation of metal-boron materials achieved by one-step reduction and doping process,utilizing boron clusters as reducing and stabilizing agents.

关键词： Boron clusters Nitrogen reduction reaction Au–B coupling

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Room-temperature synthesis of full-component APbX_(3)perovskite nanocrystal inks for optoelectronic applications

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Journal of Energy Chemistry 2024年第5期92卷 87-94页

作者： Xinyu Zhao Du Li Xuliang Zhang Hehe Huang Chenyu Zhao Wanli Ma Jianyu Yuan Institute of Functional Nano&Soft Materials(FUNSOM) Soochow UniversitySuzhou 215123JiangsuChina Jiangsu key laboratory for Carbon-Based Functional Materials&Devices Soochow UniversitySuzhou 215123JiangsuChina Jiangsu key laboratory of advanced Negative Carbon technologies Soochow UniversitySuzhou 215123JiangsuChin

Lead halide perovskite nanocrystals(PNCs)have received great research interests due to their excellent optoelectronic properties.However,high temperature,inert gas protection and insulating long-chain ligands are used during the conventional hot-injection synthesis of PNCs,which limits their practical applications.In this work,we first develop a simple and scalable polar-solvent-free method for the preparation of full-component APbX_(3)(A=Cs,methylammonium(MA),formamidinium(FA),X=Cl,Br,I)PNCs under ambient condition.Through an exothermic reaction between butylamine(BA)and propionic acid(PA)short ligands,the PbX_(2) precursors could be well dissolved without use of any polar solvent.Meanwhile,the relatively lower growth rate of PNCs in our room-temperature reaction enables us to modulate the synthetic procedure to enhance the scalability(40-fold)and achieve large-scale synthesis.The resultant short ligands passivated PNC inks are compatible with varying solution depositing technique like spray coating for large-area film.Finally,we showcase that adopting the as-prepared MAPbI_(3) PNC inks,a self-powered photodetector is fabricated and shows a high photoresponsivity.These results demonstrate that our ambient-condition synthetic approach can accelerate the preparation of tunable and ready-to-use PNCs towards commercial optoelectronic applications.

关键词： Room-temperaturesynthesis Perovskite nanocrystals Short-chainligands Large-scale Photodetector

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