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Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1675-1689页

作者： Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo Department of Immunology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Collaborative Innovation Center for Biotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Department of Lung Cancer Surgery Tianjin Medical University General HospitalTianjin 300052China Immunology Research Center National Health Research InstitutesZhunanMiaoliTaiwanROC Department of Immunology Nankai UniversityTianjin 300071China

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung cancer.Cancer stem cells(CSCs)have been identified as a crucial player in immunotherapy-related resistance.Ferroptosis,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy.Metabolic adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive.Here,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung cancer.Mechanistically,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A expression.The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in CSCs.Significantly,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关键词： immunotherapy metabolism peroxidation

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ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3523-3535页

作者： Xiao-Hui Ma Jiang-Han-Zi Liu Chun-Yu Liu Wan-Yang Sun Wen-Jun Duan Guan Wang Hiroshi Kuriara Rong-Rong He Yi-Fang Li Yang Chen Hongcai Shang Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibilty Jinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of PharmacyJinan UniversityGuangzhou 510632China international Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE) Jinan UniversityGuangzhou 510632China institute of Traditional Chinese Medicine Xinjiang Medical UniversityUrumqi 830054China Sinnovation Center of Nursing Research Nursing Key Laboratory of Sichuan ProvinceState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China College of Pharmacy Guangzhou University of Chinese Medicine Guangzhou 510405China Key Laboratory of Chinese Internal Medicine of Ministry of Education Dongzhimen HospitalBeijing University of Chinese Medicine100700 BeijingChina

Myocardial ischemia/reperfusion(/R)injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to various forms of cell death.It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase.Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids(PUFA)-phospholipids in myocardial cells,which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase.Using animal and in vitro models,the crucial lipid species in I/R injury were identifed to be oxidized PUFAs enriched phosphatidylethanolamines.Using multi-omics,arachidonic acid 15-lipoxygenase-1(ALOx15)was identified as the primary mediator of ischemia-provoked phospholipid peroxidation,which was further confirmed using chemogenetic approaches.Collectively,our results reveal that ALOx15 induction in the ischemia phase acts as a"burning point"to ignite phospholipid oxidization into ferroptotic signals.This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of V/R injury.

关键词： peroxidation ischemia damage

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Chiral Betaine-Mediated Asymmetric peroxidation-Kinetic Resolution Cascade for the Synthesis of Optically Pure Peroxides

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CCS Chemistry 2023年第7期5卷 1509-1516页

作者： Xiangyuan Liu Kang Du Jisheng Luo Li Deng Department of Chemistry Zhejiang UniversityHangzhou 310027 Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province Department of ChemistrySchool of Science and Research Center for Industries of the FutureWestlake UniversityHangzhou 310030

An array of natural products bearing chiral peroxide motifs display antitumor,anticancer,and antiparasitic activities.However,there are very few catalytic asymmetric syntheses of chiral peroxides.Moreover,effective catalysts for asymmetric catalytic peroxidations are limited to chiral amines.To further expand synthetic access to chiral peroxides,the development of new catalysts realizing catalytic asymmetric peroxidation is highly desirable yet challenging.We report here a catalytic asymmetric peroxidation of anα,β-unsaturated triflone-kinetic resolution cascade reaction,which furnishes chiral peroxides in greater than 99.9%ee.The realization of this cascade reaction resulted from the development of two betaines as novel catalysts for chiral peroxide synthesis;one betaine promoted enantioselective peroxidation ofα,β-unsaturated triflones via conjugate addition affording peroxides in 80-92%ee,while the other betaine catalyzed kinetic resolution of the newly generated chiral peroxides to further increase the ee to greater than 99.9%.

关键词： chiral peroxide peroxidation kinetic resolution betaine optically pure triflone

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Protective Effect of Naringenin on Acute Myocardial Ischemia-reperfusion Injury in Rats

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Medicinal Plant 2024年第3期15卷 50-52页

作者： Xia ZHANG Ping ZHOU Juan LI Zhaojun XIANG Qianqian LUO Qing DENG Department of Neurosurgery Taihe Hospital of Shiyan CityHubei University of MedicineShiyan 442000China Gynecology and Obstetrics Taihe HospitalHubei University of MedicineShiyan 442000China

[Objectives]To investigate the protective mechanism of naringenin on acute myocardial ischemia-reperfusion injury(AMI-RI)in Sprague-Dawley(SD)rats.[Methods]A total of 32 SD rats with AMI-RI model construction were randomly divided into AMI-RI model control group and citrus pigment A/B/C groups(n=8).The naringenin A,B,and C groups were administrated 20,40 and 80 mg/(kg•d)for 10 d.The AMI group served as the negative control and was not treated.At the conclusion of the treatment regimen,a sample of intraventricular blood was collected for the purpose of measuring lactate dehydrogenase(LDH),glutathione peroxidase(GLH-PX),nitric oxide(NO),and superoxide dismutase(SOD)levels.Additionally,myocardial tissue was identified within the ischemic region.The content of malondialdehyde(MDA)was determined by inducing nitric oxide synthase(iNOS)and endodermal nitric oxide synthase(eNOS)positive cells in the left anterior descending coronary artery.[Results]Following citrus treatment,the contents of GLH-PX and SOD in ventricular blood of the citrus B group were found to be significantly elevated,while the contents of NO and LDH in myocardial MDA and ventricle were observed to be significantly reduced.The number of eNOS-positive cells was significantly increased,while the number of iNOS-positive cells was significantly decreased.The difference was statistically significant when compared with the AMI-RI group(Pperoxidation during AMI-RI by increasing SOD activity,naringenin may also affect the synthesis and release of NO by regulating eNOS and iNOS,thereby achieving protection against AMI-RI.One effect is enhanced as the dose of the drug increases.

关键词： Rat Naringenin Acute myocardial ischemia-reperfusion Lipid peroxidation Inducible/endothelial nitric oxide synthase

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Effect of supplementing layer hen diet with phytogenic feed additives on laying performance, egg quality, egg lipid peroxidation and blood biochemical constituents

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Animal Nutrition 2018年第4期4卷 394-400页

作者： Reham Abou-Elkhair Shaimaa Selim Eman Hussein Department of Nutrition and Clinical Nutrition Faculty of Veterinary Medicine University of Sadat City Department of Nutrition and Clinical Nutrition Faculty of Veterinary Medicine University of Menoufia Department of Poultry Production Faculty of Agriculture University of Menoufia

This study was conducted to evaluate the effects of supplementing laying hen diet with phytogenic additives on laying performance, egg quality, blood constituents and egg lipid peroxidation. Two hundred Lohmann Brown Lite laying hens were randomly allotted to 4 dietary treatments: control(without phytogenic additive), fennel seeds(5 g/kg), black cumin seeds(5 g/kg) and hot red pepper(5 g/kg).Each of the 4 diets was fed to 5 replicates of 10 hens for 8 weeks. No significant differences were observed in body weight or feed intake between the groups. Dietary inclusion of fennel followed by red pepper improved(P < 0.05) egg weight, egg production, egg mass and feed conversion ratio compared with control. Higher yolk shape index, shell and albumen weight percentages and Haugh unit(P < 0.05)were recorded in the fennel supplemented group compared with control. The egg yolk color score increased by the addition of fennel or hot red pepper in laying hen diets compared with control. The inclusion of black cumin or hot red pepper decreased serum and egg yolk cholesterol and malondialdehyde concentrations(P < 0.05) compared with control. Serum aspartate aminotransferase concentration was lower in black cumin group(P < 0.05) than in other treatments. In conclusion, the best laying performance and egg quality were obtained by dietary inclusion of fennel, followed by hot red pepper and black cumin. Dietary supplementation of black cumin or red pepper may lead to the development of low-cholesterol concentration and better antioxidant capacity of eggs.

关键词： Phytogenic additives Egg quality Hepatoprotective activity Lipid peroxidation Cholesterol Laying hens

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A study on relationship of nitric oxide,oxidation,peroxidation,lipoperoxidation with chronic cholecystitis

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World Journal of Gastroenterology 2000年第4期6卷 501-507页

作者： Jun Fu Zhou Dong Cai You Gen Zhu Jin Lu Yang Cheng Hong Peng Yang Hai Yu The Second Affiliated Hospital of Medical College of Zhejiang University Hangzhou 310009ZhejiangChina The People’s Hospital of Jinhua City Jinhua 321000ZhejiangChina

AIM To study relationship of injury induced bynitric oxide,oxidation,peroxidation,lipoperoxidation with chronic cholecystitis.METHODS The values of plasma nitric oxide(P-NO),plasma vitamin C(P-VC),plasma vitamin E(P-VE),plasma β-carotene(P-β-CAR),plasmalipoperoxides(P-LPO),erythrocyte superoxidedismutase(E-SOD),erythrocyte catalase(E-CAT),erythrocyte glutathione peroxidase(E-GSH-Px)activities and erythrocyte lipoperoxides(E-LPO)level in 77 patients with chronic cholecystitisand 80 healthy control subjects were determined,differences of the above average values betweenthe patient group and the control group anddifferences of the average values betweenpreoperative and postoperative patients wereanalyzed and compared,linear regression andcorrelation of the disease course with the abovedetermination values as well as the stepwiseregression and correlation of the course with thevalues were analyzed.RESULTS Compared with the control group,theaverage values of P-NO,P-LPO,E-LPO weresignificantly increased(Pperoxidation and lipoperoxidation.

关键词： nitric oxide oxidation peroxidation ipoperoxidation chronic cholecystitis

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Administration of Fenugreek Seed Extract Produces Better Effects in Glibenclamide-Induced Inhibition in Hepatic Lipid peroxidation: An in vitro Study

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Chinese Journal of Integrative Medicine 2019年第4期25卷 278-284页

作者： Sharma Neha Kar Anand Panda Sunanda School of Life Sciences Devi Ahilya UniversityTakshashila CampusIndore452017India

Objective: To evaluate the comparative effects of fenugreek(Trigonel a foenum graecum) seed extract(FSE) alone and in combination with an antidiabetic conventional medicine,glibenclamide(GLB),on the inhibition of in vitro lipid peroxidation(LPO) in liver,the major target organ of a drug.Methods: LPO was induced by ferrous sulphate(Fe So4),hydrogen peroxide(H2 O2) and carbon tetrachloride(CCl4) and the effects of test seed extract and/or GLB were evaluated.Results: While Fe So4,H2 O2 and CCl4 markedly enhanced the hepatic LPO,simultaneous administration of FSE reduced it in a concentration dependent manner.However,when both FSE and GLB were added to the incubation mixture,chemical y induced hepatic LPO was further inhibited.The test extract also exhibited high antioxidative activity in 1,1-diphenyl-2-picrylhydrazyl radical and in 2,2'-azino-bis,3-ethylbenzothiazoline-6-sulphonic acid radical scavenging assays.Conclusion: FSE therapy in moderate concentration along with a hypoglycemic drug may prove to be advantageous in ameliorating diabetes mel itus and other diseases that are LPO mediated.

关键词： fenugreek glibenclamide antioxidant activity lipid peroxidation

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Gas stunning with CO_2 affected meat color,lipid peroxidation, oxidative stress, and gene expression of mitogen-activated protein kinases, glutathione S-transferases,and Cu/Zn-superoxide dismutase in the skeletal muscles of broilers

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Journal of Animal Science and Biotechnology 2018年第3期9卷 738-749页

作者： Lei Xu Haijun Zhang Hongyuan Yue Shugeng Wu Haiming Yang Zhiyue Wang Guanghai Qi Key Laboratory of Feed Biotechnology of Ministry of Agriculture & National Engineering Research Center of Biological Feed Feed Research Institute Chinese Academy of Agricultural Sciences College of Animal Science and Technology Yangzhou University

Background: Meat color and lipid peroxidation are important traits related to meat quality. CO_2 concentration is a critical factor that can affect meat quality in the commercial use of gas stunning(GS). However, the effect and mechanism of CO_2 stunning on meat color and lipid peroxidation during long-term storage remain poorly studied. We aimed to study the effects of GS methods, especial y CO_2 concentration, on meat color and meat lipid peroxidation in broilers during long-term storage at 4 °C and to explore the potential mechanism of meat color change via lipid peroxidation and the inner lipid peroxide scavenging system.Methods: Eighteen broilers were sacrificed after exposure to one of the following gas mixtures for 90 s: 40% CO_2+21% O_2+ 39% N2(G40%), 79% CO_2+ 21% O_2(G79%), or no stunning(0% CO_2, control). Meat color, serum variables,enzyme activities, and the gene expression of mitogen-activated protein kinase(MAPK), nuclear factor-erythroid2-related factor 2(Nrf2), glutathione S-transferase(GST) and superoxide dismutase(SOD) were determined.(Continued on next page)Results: The concentrations of serum triiodothyronine(T3, P = 0.03) and the ratio of serum free triiodothyronine/free thyroxine(FT3/FT4, P < 0.01) were decreased, whereas levels of serum cortisol(P < 0.01) were increased in the 40%CO_2 group compared with the control group. Additionally, the thiobarbituric acid-reactive substances(TBARS)3 d(P < 0.01) and TBARS6 d(P = 0.01) in breast meat and the TBARS3 din thigh meat(P < 0.01) were increased in the40% CO_2 group compared with the control group. Serum T3 was negatively correlated with TBARS6 dboth in the breast and thigh meat(r =-0.63, P < 0.01 and r =-0.47, P = 0.05 respectively). T3/T4 was negatively correlated with TBARS6 din the breast meat and in the thigh meat(r =-0.57, P = 0.01; and r =-0.53, P = 0.03 respectively). Compared with the control group, Lightness(L*)1 d(P = 0.03) and L*9 d(P < 0.01) were increased, whereas total chromatic aberration(E*)1 d(P = 0.05) and E*3 d(P < 0.01) wer

关键词： Antioxidant enzyme Broiler Controlled atmosphere stunning Gas stunning Lipid peroxidation MAPK/Nrf2/ARE Meat color Oxidative stress

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Antioxidant,lipid peroxidation inhibition and free radical scavenging efficacy of a diterpenoid compound sugiol isolated from Metasequoia glyptostroboides

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Asian Pacific Journal of Tropical Medicine 2014年第1期7卷 9-15页

作者： Vivek K.Bajpai Ajay Sharma Sun Chul Kang Kwang-Hyun Baek School of Biotechnology Yeungnam UniversityGyeongsanGyeongbook 712-749Republic of Korea

Objective:To investigate the antioxidant enicacy of a biologically active dilerpenoid compound sugiol isolated from Metasequoia glyptostroboides(M.glyptostroboides)in various antioxidant models.Methods:An abietane type diterpenoid sugiol,isolated from ethyl acetate extract of M.glyptostroboides cones,was analyzed for its antioxidant efficacy as reducing power ability and lipid peroxidation inhibition as well as its ability to scavenge free radicals such as 1,1-diphenyl-2-picryl hydrazyl,nitric oxide,superoxide and hydroxyl radicals.Results:The sugiol showed significant and concentration-dependent antioxidant and free radical scavenging activities.Consequently,the sugiol exerted lipid peroxidation inhibitory effect by 76.3%as compared to a-tocopherol(80.13%)and butylaled hydroxyanisole(76.59%).In addition,the sugiol had significant scavenging activities of l,l-diphenyl-2-picryl hydrazyl,nitric oxide,superoxide and hydroxyl free radicals in a concentration-dependent manner by 78.83%,72.42%,72.99%and 85.04%,when compared to the standard compound ascorbic acid(81.69%,74.62%,73.00%and 73.79%)and a-tocopherol/butylated hydroxyanisole(84.09%,78.61%,74.45%and 70.02%),respectively.Conclusions:These findings justify the biological and traditional uses of M.glyptostroboides or its secondary metabolites as confirmed by its promising antioxidant efficacy.

关键词： Sugiol Diterpenoid Antioxidant Free radicals Lipid peroxidation

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Lipid peroxidation: Its effects on the formulation and use of pharmaceutical emulsions

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Asian Journal of Pharmaceutical Sciences 2017年第5期12卷 401-411页

作者： Ramona Khanum Haema Thevanayagam School of Postgraduate Studies International Medical University (IMU)

Pharmaceutical delivery systems are developed to improve the physicochemical properties of therapeutic compounds. Emulsions are one of these drug delivering systems formulated using water, oils and lipids as main ingredients. Extensive data are usually generated on the physical and chemical characteristics of these oil-in-water and lipid emulsions. However, the oxidative tendency of emulsions is often overlooked. Oxidation impacts the overall quality and safety of these pharmaceutical emulsions. Additionally, introducing oxidatively unstable emulsions into biological systems further promotes oxidation in situ. Products of these reactions then continue to pose serious harm to cells and fuel other physiological oxidation reactions. Consequently, the increase of oxidation products leads to oxidative damage to biological systems. Thus, emulsions with lower lipid peroxidation are more stable and will reduce the negative effects of oxidation in situ. Preventive measures during the formulation of emulsions are important. Many naturally occurring and cost effective substances possess low oxidation tendencies and confer oxidative protection when used in emulsions. Additionally,certain preparatory methods should be employed to reduce or better control lipid peroxidation.Finally, emulsions must be evaluated for their oxidation susceptibility using the various techniques available. Careful attention to the preparation of emulsions and assessment of their oxidative stability will help produce safer emulsions without compromising efficacy.

关键词： Drug delivery Emulsions Lipids peroxidation Oxidative stress

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