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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun Yuzhu Hu Yuanyuan Zhang Zhiyong qian xiang Gao Zhirong Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

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Transient receptor potential vanilloid 1 involved in the analgesic effects of total flavonoids extracted from Longxuejie(Resina Dracaenae Cochinchinensis)

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Journal of Traditional Chinese Medicine 2024年第3期44卷 437-447页

作者： MO Xiaoqiang CHEN Yating yin qian CHEN Haibo BAN qiang LI Jun CHEN Su YAO Jinguang Department of Stomatology Affiliated Hospital of Youjiang Medical University for NationalitiesBaise 533000China College of General Practitioners Youjiang Medical University for NationalitiesBaise 533000China College of Biomedical Engineering South-Central Minzu UniversityKey Laboratory of Cognitive Science of State Ethnic Affairs CommissionHubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and TreatmentWuhan 430074China College of Pharmacy South-Central Minzu UniversityWuhan 430074China

OBJECTIVE: To evaluate the analgesic effects of total flavonoids of Longxuejie(Resina Dracaenae Cochinchinensis)(TFDB) and explore the possible analgesic mechanism associated with transient receptor potential vanilloid 1(TRPV1).METHODS: Whole-cell patch clamp technique was used to observe the effects of TFDB on capsaicin-induced TRPV1 currents. Rat experiments in vivo were used to observe the analgesic effects of TFDB. Western blot and immunofluorescence experiments were used to test the change of TRPV1 expression in DRG neurons induced by ***: Results showed that TFDB inhibited capsaicin-induced TRPV1 receptor currents in acutely isolated dorsal root ganglion(DRG) neurons of rats and the half inhibitory concentration was(16.7 ± 1.6) mg/***(2-20 mg/kg) showed analgesic activity in the phase Ⅱ of formalin test and(0.02-2 mg per paw)reduced capsaicin-induced licking times of rats. TFDB(20 mg/kg) was fully efficacious on complete Freund's adjuvant(CFA)-induced inflammatory thermal hyperalgesia and capsaicin could weaken the analgesic effects. The level of TRPV1 expressions of DRG neurons was also decreased in TFDB-treated CFA-inflammatory pain ***: All these results indicated that the analgesic effect of TFDB may contribute to their modulations on both function and expression of TRPV1 channels in DRG neurons.

关键词： Freund's adjuvant formaldehyde capsaicin flavonoids Longxuejie(Resina Dracaenae Cochinchinensis) transient receptor potential vanilloid 1 inflammatory pain

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Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway

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Research 2024年第3期2023卷 499-511页

作者： Hongen Meng yingying Yu Enjun Xie qian Wu xiangju yin Bin Zhao Junxia Min Fudi Wang The Second Afiliated Hospital The First Affiliated HospitalInstitute of Translational MedicineScho of Public HealthZhejiang University School of MedicineHangzhouChina institute of Emergency Management Henan Polytechnic UniversityJiaozuoChina MOE Key Laboratory of Biosystems Homeostasis and Protection Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biologyand Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou 310058China.

Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular ***,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain ***,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse *** lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron *** profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of ***,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA *** a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter *** also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of ***,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO ***,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver *** results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

关键词： homeostasis metabolism expressing

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Four New Terpyridine Complexes Based Polyoxometalates with[W_(10)O_(32)]^(4-) Anions as High-Efficiency Dual-Site Catalysis for Thioether Oxidation Reaction

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Chinese Journal of Chemistry 2024年第6期42卷 592-598页

作者： yin Zhang Wei-Dong Yu Fang-qian Wang xiangnan Wang Jiawan Zhou Chao Liu Jun Yan Junior Education Department Changsha Normal UniversityChangshaHunan410100 China School of Science Hunan University of Technology and BusinessChangshaHunan410000 China College of Chemistry and Chemical Engineering Central South UniversityChangshaHunan410000 China

Polyoxometalates modified with complex cations have attracted increasing attention because of the fascinating properties and the controllable *** adjusting the synthesis conditions,four new terpyridine complexes based hybrid POMs,[(TPY-H)CuCl]_(4)[W_(10)O_(32)]·2DMF·2H_(2)O(1),[(TPY-H)Cu(DMSO)(H_(2)O)]_(2)[W_(10)O_(32)]·2H_(2)O(2),[(TPY-H)_(2)Cu]_(2)[W_(10)O_(32)]·6DMSO·8H_(2)O(3) and[(TPY-Br)CuCl(DMSO)(H_(2)O)]_(2)[(TPY-Br)CuCl]_(2)[W_(10)O_(32)]·2DMSO·4H_(2)O(4),were prepared by using‘one-pot’***-crystal X-ray diffraction analyses,infrared radiation,etc.,revealed the structural composition of compounds 1—4,which indicates that synthesis conditions have a directional regulatory effect on the compounds *** oxidation catalytic reactions show 1—4 have good catalytic activities,and powder X-ray diffraction and thermogravimetry analysis show 1—4 have superduper catalytic ***,4 has better catalytic activity because of the different structure of terpyridine ***,a possible mechanism of dual-site catalysis by both cations and anions is proposed.

关键词： Polyoxometalates Terpyridine complexes Thioether oxidation Dual-site catalysis Clusters

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Hypoglycemic mechanism of Tegillarca granosa polysaccharides on type 2 diabetic mice by altering gut microbiota and regulating the PI3K-akt signaling pathwaye

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Food Science and Human Wellness 2024年第2期13卷 842-855页

作者： Qihong Jiang Lin Chen Rui Wang yin Chen Shanggui Deng Guoxin Shen Shulai Liu Xingwei xiang College of Food Science and Technology Zhejiang University of TechnologyHangzhou 310014China Key Laboratory of Marine Fishery Resources Exploitment&Utilization of Zhejiang Province Hangzhou 310014China National R&D Branch Center for Pelagic Aquatic Products Processing(Hangzhou) Hangzhou 310014China Institute of Sericultural and Tea Zhejiang Academy of Agricultural SciencesHangzhou 310021China College of Food and Pharmacy Zhejiang Ocean UniversityZhoushan 316000China

Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human *** investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and ***(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and *** could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin ***-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin *** increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid *** study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.

关键词： Tegillarca granosa polysaccharide Type 2 diabetes mellitus Glycolipid metabolism PI3K/Akt signaling pathway

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Transcriptional regulation of MdPIN7 by MdARF19 during gravityinduced formation of adventitious root GSA in self-rooted apple stock

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Horticultural Plant Journal 2024年第5期10卷 1073-1084页

作者： Zenghui Wang Xuemei Yang Linyue Hu Wei Liu Lijuan Feng xiang Shen Yanlei yin Jialin Li Shandong Institute of Pomology Tai'anShandong 271000China School of Biological Science and Technology University of JinanJinanShandong 250022China State Key Laboratory of Crop Biology Key Laboratory of Biology and Genetic Improvement of Horticultural Crops(Huanghuai Region)Ministry of AgricultureCollege of Horticulture Science and EngineeringShandong Agricultural UniversityTai'anShandong 271018China

Self-rooted apple stock is widely used for apple ***,the shallowness of the adventitious roots in self-rooted apple stock leads to poor performance in the barren orchards of *** is because of the considerable difference in the development of a gravitropic set-point angle(GSA)between self-rooted apple stock and seedling ***,it is crucial to study the molecular mechanism of adventitious root GSA in self-rooted apple stock for breeding self-rooted and deep-rooted apple rootstock *** apple auxin response factor MdARF19 functioned to establish the adventitious root GSA of self-rooted apple stock in response to gravity and auxin ***19 bound directly to the MdPIN7 promoter,activating its transcriptional expression and thus regulating the formation of the adventitious root GSA in 12-2 self-rooted apple ***,MdARF19 influenced the expression of auxin efflux carriers(MdPIN3 and MdPIN10)and the establishment of adventitious root GSA of self-rooted apple stock in response to gravity signals by direct activation of *** findings provide new information on the transcriptional regulation of MdPIN7 by auxin response factor MdARF19 in the regulation of the adventitious root GSA of self-rooted apple stock in response to gravity and auxin signals.

关键词： Apple Self-rooted stock Gravity MdARF19 MdPIN7 Gravitropic set-point angle Transcriptional regulation

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Insights into microbiota community dynamics and flavor development mechanism during golden pomfret(Trachinotus ovatus)fermentation based on single-molecule real-time sequencing and molecular networking analysis

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Food Science and Human Wellness 2024年第1期13卷 101-114页

作者： Yueqi Wang qian Chen Huan xiang Dongxiao Sun-Waterhouse Shengjun Chen Yongqiang Zhao Laihao Li Yanyan Wu Key Laboratory of Aquatic Product Processing Ministry of Agriculture and Rural Affairs of The People’s Republic of ChinaNational R&D Center for Aquatic Product ProcessingSouth China Fisheries Research InstituteChinese Academy of Fishery SciencesGuangzhou 510300China Co-Innovation Center of Jiangsu Marine Bio-industry Technology Jiangsu Ocean UniversityLianyungang 222005China School of Chemical Sciences The University of AucklandAuckland 92019New Zealand Collaborative Innovation Center of Seafood Deep Processing Dalian Polytechnic UniversityDalian 116034China

Popular fermented golden pomfret(Trachinotus ovatus)is prepared via spontaneous fermentation;however,the mechanisms underlying the regulation of its flavor development remain *** study shows the roles of the complex microbiota and the dynamic changes in microbial community and flavor compounds during fish ***-molecule real-time sequencing and molecular networking analysis revealed the correlations among different microbial genera and the relationships between microbial taxa and volatile *** underlying flavor development were also elucidated via KEGG based functional ***,Shewanella,and Staphylococcus were the dominant microbial ***-nine volatile compounds were detected in the fermented fish samples,with thirteen identified as characteristic volatile compounds(ROAV>1).Volatile profiles resulted from the interactions among the microorganisms and derived enzymes,with the main metabolic pathways being amino acid biosynthesis/metabolism,carbon metabolism,and glycolysis/*** study demonstrated the approaches for distinguishing key microbiota associated with volatile compounds and monitoring the industrial production of high-quality fermented fish products.

关键词： Fermented golden pomfret Microbiota community Volatile compound Co-occurrence network Metabolic pathway

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Could the EU carbon border adjustment mechanism promote climate mitigation?An economy-wide analysis

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Advances in Climate Change Research 2024年第3期15卷 557-571页

作者： Kun ZHANG Yun-Fei YAO xiang-Yan qian Yu-Fei ZHANG Qiao-Mei LIANG Yi-Ming WEI College of Economics and Management Beijing University of TechnologyBeijing 100124China Center for Energy and Environmental Policy Research Beijing Institute of TechnologyBeijing 100081China School of Management and Economics Beijing Institute of TechnologyBeijing 100081China Beijing Key Laboratory of Energy Economics and Environmental Management Beijing 100081China Sinopec Research Institute of Petroleum Engineering SinopecBeijing 100101China College of Economics and Management Nanjing Agricultural UniversityNanjing 210095China

Due to concerns about carbon leakage and sectoral competitiveness,the European Union(EU)proposed implementing the carbon border adjustment mechanism(CBAM).The effectiveness and potential negative consequences of CBAM have aroused extensive *** the perspective of the economy-wide analysis,this study uses a global computable general equilibrium model to explore the rationality of CBAM from the aspects of socioeconomic impact and the effects of promoting climate ***,the potential alternative mechanism of CBAM is *** results show that CBAM can reduce the EU's gross domestic product(GDP)loss;however,the GDP loss in all other regions ***,CBAM raises household welfare losses in most regions,including the ***,although CBAM can reduce the marginal abatement cost in eight regions,it comes at the cost of greater economic ***,the economic and household welfare cost of raising emissions reduction targets in regions like the USA and Japan is substantially higher than the impact of passively accepting the CBAM;therefore,CBAM's ability to drive ambitious emission reduction initiatives may be ***,for the potential alternative mechanism,from the perspective of reducing economic cost and household welfare losses,the EU could implement domestic tax cuts in the short-term and promote global unified carbon pricing in the long-term.

关键词： Border adjustment mechanism Computable general equilibrium model Carbon price Climate policy Global carbon pricing

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Copper-catalyzed conjugate addition of allene-derived nucleophiles to alkenyl-substituted carboxamides

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Chinese Chemical Letters 2024年第3期35卷 239-242页

作者： Bin Fu Yue Zhao Xiuping Yuan Yanfei Li Jianjun yin Simin Wang Tao Xiong qian Zhang Jilin Province Key Laboratory of Organic Functional Molecular Design&Synthesis Department of ChemistryNortheast Normal UniversityChangchun 130024China State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China School of Chemistry and Environmental Engineering Changchun University of Science and TechnologyChangchun 130012China

Catalytic Michael addition reaction represents a fundamental importance in organic synthetic *** corresponding conversions toward intrinsically low reactive enamide remains an ongoing *** herein report a copper-catalyzed conjugate addition of allenes toβ-substituted alkenyl amides,one of the most challenging Michael *** present method utilizes readily available allenes as the latent carbon-based nucleophiles and simple,commonβ-substituted alkenyl amides as starting materials,unlike previous methods that usually preinstall an activating group to improve the reactivity of amide or uses highly reactive stoichiometric quantities of ***,this approach shows good functional group compatibility and can be implemented under mild reaction conditions with excellent level of chemo-and regioselectivities.

关键词： CuH catalysis Allenes Unsaturated amide Conjugate addition Regioselectivity

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Investigations of methane adsorption characteristics on marine-continental transitional shales and gas storage capacity models considering pore evolution

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Petroleum Science 2024年第4期21卷 2273-2286页

作者： Chen-Gang Lu Xian-Ming Xiao Zhen-qian Xue Zhang-Xin Chen yin-Tao Dong Yue Feng Gang Li School of Energy Resources China University of Geosciences (Beijing) School of Civil and Environmental Engineering Nanyang Technological University Chemical and Petroleum Engineering University of Calgary Eastern Institute of Technology (tentative) CNOOC Research Institute

Methane adsorption is a critical assessment of the gas storage capacity(GSC) of shales with geological conditions. Although the related research of marine shales has been well-illustrated, the methane adsorption of marine-continental transitional(MCT) shales is still ambiguous. In this study, a method of combining experimental data with analytical models was used to investigate the methane adsorption characteristics and GSC of MCT shales collected from the Qinshui Basin, China. The Ono-Kondo model was used to fit the adsorption data to obtain the adsorption parameters. Subsequently, the geological model of GSC based on pore evolution was constructed using a representative shale sample with a total organic carbon(TOC) content of 1.71%, and the effects of reservoir pressure coefficient and water saturation on GSC were explored. In experimental results, compared to the composition of the MCT shale, the pore structure dominates the methane adsorption, and meanwhile, the maturity mainly governs the pore structure. Besides, maturity in the middle-eastern region of the Qinshui Basin shows a strong positive correlation with burial depth. The two parameters, micropore pore volume and non-micropore surface area, induce a good fit for the adsorption capacity data of the shale. In simulation results, the depth,pressure coefficient, and water saturation of the shale all affect the GSC. It demonstrates a promising shale gas potential of the MCT shale in a deeper block, especially with low water saturation. Specifically,the economic feasibility of shale gas could be a major consideration for the shale with a depth of 60% in the Yushe-Wuxiang area. This study provides a valuable reference for the reservoir evaluation and favorable block search of MCT shale gas.

关键词： High-pressure methane adsorption Marine-continental transitional shale gas Ono-Kondo model Adsorption thermodynamics Gas storage capacity model

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